AIDS Vaccines, HIV Receptors, and AIDS Research [1 ed.] 9781608764808, 9781606920749

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Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

AIDS VACCINES, HIV RECEPTORS, AND AIDS RESEARCH

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AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

AIDS VACCINES, HIV RECEPTORS, AND AIDS RESEARCH

LAWRENCE B. KENDOW

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EDITOR

Nova Biomedical Books New York

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication.

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This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA AIDS vaccines, HIV receptors, and AIDS research / Lawrence B. Kendow (editor). p. ; cm. Includes bibliographical references. ISBN 978-1-60876-480-8 (E-Book) 1. AIDS vaccines. 2. HIV (Viruses) I. Kendow, Lawrence B. [DNLM: 1. Acquired Immunodeficiency Syndrome. 2. AIDS Vaccines. 3. Receptors, HIV. 4. Research. WC 503 A28845 2008] QR189.5.A33A43 2008 615'.372--dc22 2008030427

Published by Nova Science Publishers, Inc.

New York

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

CONTENTS Preface Chapter 1

Safe and Effective HIV Vaccines Since 1999 Jeremiah O. A. Abalaka

Chapter 2

AIDS: A Mucosal Approach to a Mucosal Infection Lesley Ann Bergmeier

Chapter 3

Transmission of HIV from Dendritic Cells to CD4+ T Cells: A Promising Target for Vaccination and Therapeutic Intervention Yasuko Tsunetusug-Yokota

1 87

117

Chapter 4

The Globalization-AIDS-Poverty Syndrome in Africa Pádraig Carmody and Glen Elder

129

Chapter 5

Youth Sexuality in the Context of HIV/AIDS in South Africa Karl Peltzer, Supa Promtussananon and Teresa-Ann B. Mashego

153

Chapter 6

Vitamin E in the Context of HIV Disease: Current Knowledge and Perspectives Giovana Lótici Baggio and Celso Spada

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vii

Chapter 8

CCR5 Gene Expression and Polymorphism as Potential Prognostic Markers of the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation Katarzyna Bogunia-Kubik Emerging Roles of SDF-1α -Cxcr4 Axis in Vertebrate Development Vladimir Korzh and Shang-Wei Chong

Index

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241

271

301 313

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PREFACE Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a set of symptoms and infections resulting from the damage to the human immune system caused by the human immunodeficiency virus (HIV). This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids.This book presents new and important research in the field from around the globe. Chapter 1 – Since the controversial (some would say, unfortunate) press conference announcement on a Monday afternoon, April 23, 1984 by Margaret Heckler, then US Secretary of Health, Education and Welfare, that the laboratory of Prof. Robert Gallo of the National Cancer Institute had discovered the virus (now called Human Immunodeficiency Virus, HIV) responsible for causing the Acquired Immunodeficiency Syndrome (AIDS), researchers worldwide have been searching in vain for effective and safe vaccines (preventive and therapeutic) against the virus. The search for these vaccines has cost hundreds of billions of dollars. Meanwhile, millions have died, and are still dying of HIV/AIDS especially in sub-Saharan Africa that harbours about 70% of the world’s HIV/AIDS cases. The disease is still spreading with devastating morbidity, mortality and grave socio-economic consequences in the countries affected. Those infected by the HIV are highly stigmatized and ostracized everywhere in the world. HIV vaccine ‘experts’ and researchers as well as the United Nations have produced guidelines on HIV preventive vaccine research and development. They have all declared that humanity is still at least a decade away from the dawn of effective and safe HIV vaccines. This chapter not only critically examines these issues but analyzes the modern immunological concepts of HIV and its vaccine development strategy to show that the road from 1984 till now is indeed overgrown by numerous and bizarre weeds of assertions, dogmas, approaches and conclusions that have contributed in no small measure to the extant failure at effective and safe HIV vaccine research and development. By paying appropriate attention to these weeds

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Lawrence B. Kendow

hampering progress, the author, using just his family resources and working single-handedly, has been able to conceive, develop and apply effective and safe HIV vaccines since 1999. Chapter 2 - The past quarter of a century has been witness to a devastating pandemic taking the lives of more than 25 million people and to date leaving more than 40 million infected with a virus which produces an essentially mucosal disease. The majority of Human Immunodeficiency virus (HIV) infections occurring in developing countries, where AIDS has their deepest economic impact, are acquired mucosally either through sexual activity or by mother to child transmission. It has been estimated that greater than 75% of HIV infections are transmitted by the mucosal route. The pharmaceutical industry has made huge advances in drug therapies such as HAART which not only save and prolong life but enhance the quality of life of infected individuals. However, these therapies are not universally available and in particular their cost presents difficulties to HIV infected people in economically impoverished countries. The need for a vaccine has never been more urgent and our understanding and ability to manipulate the mucosal immune system stands at the forefront of the next generation of vaccine candidates, or indeed microbicidal agents. However, the prevalent DNA prime viral boost strategy aims to elicit cytotoxic lymphocytes (CTL) against HIV but this approach is undermined by the rapid mutation of HIV which thereby escapes CTL control. Neutralising antibodies are also subject to viral escape. Moreover, these systemic approaches often fail to induce responses at the mucosal barrier. The target cell of the HIV virus is the CD4+ T cell and within days of infection a catastrophic crash in the numbers of these cells in the gut heralds the beginning of an immunodeficiency, which is the signature of the disease. In the past decade the co-receptors for HIV have been described and the unique resistance of individuals with the Δ32 deletion and the effect of allo-responses have led to a re-examination of the experiments of nature that have helped towards an understanding of the correlates of protection required of a successful vaccine. Both innate and adaptive immune responses contribute to protection from infection in these individuals, so that a successful vaccine may need to recapitulate some or all of these correlates of protection. This review will examine the mechanisms of mucosal transmission in both humans (HIV) and animal models (Simian Immunodeficiency Virus -SIV) and describe the correlates of protection which have been induced by successful experimental vaccination using both cognate viral antigens and alloimmunisation in the context of mucosal immunity to HIV /SIV. The importance of mucosal adjuvants will be investigated and the contribution of innate antiviral mechanisms will be described. What does a vaccine have to do at the site of transmission? Do we need antibodies? If so, IgG or SIgA? Are mucosal cytotoxic cells an absolute requirement for protection at mucosal surfaces? Can multifunctional T cells be induced at mucosal sites? The answer to some of these questions is known and the mucosal context will be the central theme of this paper. Chapter 3 - Dendritic cells (DCs) bridge innate and acquired immunity and thus hold a sentinel role in the immune response. In HIV infection, however, this property of DCs holds opposing implications. In order for a vaccine to be effective, antigen presentation must be sufficiently robust. On the other hand, DCs are susceptible to HIV infection and close contact of HIV-infected DCs with CD4+ T cells contributes to efficient dissemination of HIV through

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Preface

ix

the body. Here I discuss current understanding of the role of DCs in HIV infection, and the implications in developing a vaccine against HIV, which would protect both DCs and HIVspecific CD4+ T cells. Chapter 4 – Geographically speaking, AIDS the usually fatal result of an HIV infection, is primarily instantiated in parts of sub-Saharan Africa, which also contains two-thirds of the world’s cases of HIV infection. There were more than 2.1 million AIDS deaths there in 2006, more than 70% of the world’s total from complications related to HIV. Put simply, people live with HIV in most parts of the world but tend to get infected by HIV more often and die more quickly of AIDS in sub-Saharan Africa. A fifteen year old boy in Botswana has over a 90% chance of dying of AIDS (UNAIDS, 2000 cited in Barnett and Whiteside, 2006). While statistics such as these are well known, what is surprising is that suffering and death on this scale was foreseen and allowed to develop (for examples of early warnings pertaining to HIV in sub-Saharan Africa see Seale 1986; Caldwell, Caldwell and Quiggin 1989; Barnett and Blaikie 1992; the links between migrant labor in sub-Saharan Africa and HIV see Jochelson et al., 1991; HIV and gender inequality in sub-Saharan Africa see McFadden 1992). More recent responses from international organizations like the World Health Organization, private foundations like the Bill and Melinda Gates Foundation, and state actors like the European Union and the United States are largely responses to the work of highly organized coalitions of the sick and dying who focussed global attention on the pandemic. The AIDS Coalition to Unleash Power (ACT UP) and the Treatment Action Campaign are two well-known examples. These successes notwithstanding, the depth of the current crisis remains a stark testament to the failure of institutions across multiple scales to respond adequately to treat and halt the virus. Our interest here is in the dialectical ways in which the neoliberal globalization has been implemented and the human immonodefiecieny virus has spread producing a GlobalizationAIDS-poverty syndrome in sub-Saharan Africa. We are interested in interrogating the multiple forms of agency and scalar processes contained in the verb “acquired” in AIDS. For example, to date biomedical approaches to the prevention of HIV have been premised on the liberal self-determining individual who is “free to choose” health behaviours (Fee and Krieger, 1994 cited in Sember et al., 2003), to the neglect of structural factors. Chapter 5 - Dowsett (2003) notes that by far, the vast majority of non-biomedical research on HIV/AIDS has been behavioural research, usually by survey methods, counting people’s sex acts, partners, preferences, places, times and reasons for sex, and assessing levels of risk for HIV infection, revealing the dominance of seeing sex largely as behaviours. However, the notion of behaviours denudes sex of all meaning and pleasure. It neglects, as a result, how meaning and pleasure rely on context, how context exemplifies culture, and how culture is structured by history and discourse. When we drive our understanding of the epidemic by behaviours alone, we fail to comprehend that many of the social determinants of behaviour lie beyond the conscious apprehension of immediate acts and volitions, i.e., sexual behaviours are socially embedded practices. If we fail to understand the determinants of HIV risk and vulnerability as profoundly social- and by social is meant relational, contextual, cultural, political, economic, historical, symbolic and discursive- we fail to understand best how to intervene.

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Lawrence B. Kendow

Also, in such behavioural surveys, we are often concerned more with the sex of the sexual partner than the meaning of sex without a condom or an understanding of which circumstances within a sexual economy structure risk as, say, pleasure or intimacy, or social membership or an act of self-actualisation. Research undertaken in the mid-1990’s among young people in seven developing countries revealed the importance of changing sexual meanings, sexual cultures and sexual identities in the patterns of sexual activity, forms of partnering, and meanings of sexual safety for young people within rapidly changing cultures (Dowsett, Aggleton and Abega, 1998). Chapter 6 - Low serum antioxidant levels are largely seen in HIV infected patients, accompanied by a simultaneous overproduction of reactive oxygen intermediates, characterizing a chronic state of oxidative stress. The chronic immune activation that occurs since the initial stages of the infection is responsible for the increase in the production of reactive oxygen intermediates, which favor viral replication through activation of nuclear transcription factors, like NF-κB and AP-1, which are obligatory for HIV transcription. Besides increasing HIV replication, the elevated production of reactive oxygen species is associated with drug toxity and depletion of lymphocytes by apoptosis. The high levels of apoptosis observed in these patients are responsible for the commitment of the immune system and progression to AIDS, moreover, there is a direct relationship between deficiencies of nutrients such as vitamins E, C, A, B6, and B12 and a decline in CD4 T-cell count in HIV seropositive patients. Once dysfunctions of the digestive tract, such as diarrhea and oropharyngeal candidiasis, are common in immunocompromised patients and may be responsible for the poor absorption of vitamins ingested from the diet, the use of antioxidant supplementation could be useful in the treatment of HIV seropositive patients, adding more therapeutic alternatives and delaying disease progression. Although, more research is needed to understand the mechanisms involved in drug-to-drug interactions, especially in the concern of vitamin E and HAART. In this review we will focus on the role of vitamin E in the context of HIV infection with regard to the nutritional deficiencies and vitamin E supplementation in HIV-infected patients; the mechanisms of drug-to-drug interactions involving cytochrome P450 system; the role of vitamin E in improving conditions such as hyperlactatemia, drug toxity and dislipidemia; the potential antiviral activity of vitamin E and vitamin E supplementation and lymphocyte viability. Chapter 7 - Despite improvements in allogeneic hematopoietic stem cell transplantation (HSCT), acute graft-versus-host disease (GvHD) remains a significant problem after transplantation, and it is still a major cause of post-transplant mortality. Disease progression is characterized by the differentiation of alloreactive T cells to effector cells leading to tissue damage, recruitment of additional inflammatory cell populations and further cytokine dysregulation. Chemokines, including macrophage inflammatory proteins MIP-1α (CCL3), MIP-1β (CCL4), regulated upon activation T cell expressed and secreted RANTES (CCL5), which are ligands for the CC chemokine receptor 5 (CCR5), are involved in the trafficking of leukocytes in inflammation. These chemokines play a major role in the inflammatory and immune responses that mediate allograft outcome. Their coordinated expression may be important in the directed migration of alloreactive T cells during GvHD.

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Indeed studies using murine models of acute GvHD have demonstrated the critical role of MIP-1α, MIP-1β, RANTES (CCL3-5) and CCR5 in directing T-cell infiltration into target tissues during acute GvHD. In humans, polarized Th1 cells (known to be implicated in the pathomechanism of acute GvHD) preferentially express CXCR3 and CCR5. In addition, the increasing gene-expression levels for CCR5, CXCR3, CCR1, and CCR2 were observed a few days before acute GvHD was clinically diagnosed. Another complication affecting the recipients of HSCT is Epstein-Barr Virus (EBV) reactivation. It have been suggested that EBV reactivation induces increased expression of MIP-1α, MIP-1β and RANTES (CCL3-5) and their receptor CCR5. It has been also shown that in acute EBV infection, proliferating CCR5+CD4+ T cells accumulated to very high levels. One of the mutation within the CCR5 encoding gene having some functional implications is the 32-base pair deletion mutation (CCR5Δ32). This deletion causes a shift in the reading frame, which results in a severely truncated protein that is unable to reach the cell surface, leading to complete loss of the functional CCR5 receptor in subjects homozygous for this mutation and decreased expression on heterozygous individuals. The CD3-positive cells derived from CCR5 heterozygotes have reduced surface expression of CCR5 and a weaker response to its ligands. There has been some intriguing data suggesting a potential role of the CCR5 gene polymorphism in the perpetuation of viral infections. The initial results came from the studies on HIV-1 infected patients. The presence of the CCR5Δ32 allele in these patients was found to be associated with lack of clinical symptoms in individuals homozygous for this mutation or with lower expression of CCR5 and slower progression to AIDS in heterozygous individuals. Studies in patients undergoing allogeneic HSCT have suggested the association of the CCR5 gene polymorphism with the transplant outcome, contribution to the pathogenesis of GvHD and EBV reactivation in patients after HSCT. This paper reviews the knowledge on the role of CCR5 and its ligands in allogeneic HSCT. In more detail, the aspects related with polymorphism of the CCR5 gene and the HSCT outcome are presented and discussed. Chapter 8 - The CXC chemokine receptor CXCR4 is well-known as the docking site of the HIV-1 virus in the membrane of the host cell. Although CXCR4 binds a single ligand, SDF-1α, it plays multiple roles in the development of vertebrates. In rodents, the expression pattern of the single CXCR4 gene is very dynamic reflecting the many functions of this chemokine receptor. In teleost genomes, both chemokine receptor Cxcr4 and its ligand are divided between two duplicated cxcr4 and sdf1α genes as a consequence of the species specific process called subfunctionalization, facilitating the analysis of specific gene functions in different cell lineages, tissues and organs during development. Recently, several zebrafish mutants that affect genes encoding components of the SDF1α-Cxcr4 signalling system became available. In combination with results from gene knockdown experiments, these mutants shed light on the roles of SDF1α-Cxcr4 signaling during cell migration and cell fate determination of various cell lineages. This short review will summarize the recent progress in deciphering the developmental roles of SDF1α-Cxcr4, focusing mainly on the findings in teleosts.

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In: AIDS Vaccines, HIV Receptors and AIDS Research ISBN 978-1-60692-074-9 Editor: Lawrence B. Kendow © 2008 Nova Science Publishers, Inc.

Chapter 1

SAFE AND EFFECTIVE HIV VACCINES SINCE 1999 Jeremiah O. A. Abalaka Medicrest Specialist Hospital, Abuja, Nigeria

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ABSTRACT Since the controversial (some would say, unfortunate) press conference announcement on a Monday afternoon, April 23, 1984 by Margaret Heckler, then US Secretary of Health, Education and Welfare, that the laboratory of Prof. Robert Gallo of the National Cancer Institute had discovered the virus (now called Human Immunodeficiency Virus, HIV) responsible for causing the Acquired Immunodeficiency Syndrome (AIDS), researchers worldwide have been searching in vain for effective and safe vaccines (preventive and therapeutic) against the virus. The search for these vaccines has cost hundreds of billions of dollars. Meanwhile, millions have died, and are still dying of HIV/AIDS especially in sub-Saharan Africa that harbours about 70% of the world’s HIV/AIDS cases. The disease is still spreading with devastating morbidity, mortality and grave socio-economic consequences in the countries affected. Those infected by the HIV are highly stigmatized and ostracized everywhere in the world. HIV vaccine ‘experts’ and researchers as well as the United Nations have produced guidelines on HIV preventive vaccine research and development. They have all declared that humanity is still at least a decade away from the dawn of effective and safe HIV vaccines. This chapter not only critically examines these issues but analyzes the modern immunological concepts of HIV and its vaccine development strategy to show that the road from 1984 till now is indeed overgrown by numerous and bizarre weeds of assertions, dogmas, approaches and conclusions that have contributed in no small measure to the extant failure at effective and safe HIV vaccine research and development. By paying appropriate attention to these weeds hampering progress, the author, using just his family resources and working single-handedly, has been able to conceive, develop and apply effective and safe HIV vaccines since 1999.

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2

Jeremiah O. A. Abalaka

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INTRODUCTION Poliomyelitis, one of man’s ancient diseases, was known as far back as 1580 - 1350 B.C, as recorded in an Egyptian stele during the 18th Dynasty [1]. The first effective and safe vaccine against any human and animal disease-causing micro-organisms however was not developed until about 3000 years later, in 1796. About 100 years further on, more vaccines were developed. Among these vaccines were those effective against viruses, a group of micro-organisms completely unknown to humanity at the time the vaccines were developed. More vaccines were developed especially in the 1950’s and 1960’s . Smallpox, rabies, diphtheria, tetanus, pertussis, polio, measles, chickenpox, mumps, rubella, hepatitis A and B, Haemophilus influenzae B, yellow fever and cholera vaccines were all developed empirically before cell mediated immunity (CMI) was developed. In fact, the now vast fields of Immunology and Virology are recent specialties developed in the last half of the last century. All the successful vaccines against the viruses that cause the acute infectious diseases of infancy and childhood employ either inactivated or live attenuated viruses. Inactivation is achieved by heating, exposure to ultraviolet light or gamma radiation, treatment with inactivating agents such as formaldehyde or acetyl-ethylene-imine, or the use of denaturing agents such as urea or proteolytic enzymes. Live attenuated vaccines are usually developed in the laboratories using other animals, monkey or human cell culture lines or chick embryos followed by purification. Stabilizers, adjuvants and preservatives are usually added to both types of vaccines. Vaccines from inactivated viruses or bacteria are more likely to survive at ambient room temperatures below 200C. Live vaccines however need to be stored refrigerated, frozen or freeze-dried [2]. Vaccines usually generate high titres of neutralizing antibodies to prevent infection upon exposure to the wild virus, and this is the way new vaccines are traditionally tested. The vaccine doses and regimens are first tested in normal volunteers for their capacity to invoke high titres of neutralizing antibodies. Then, the vaccine and placebo are introduced into a population where the incidence of infection is high, and the frequencies of infections in the vaccinated group and in the placebo control group are compared. This approach requires a reasonably high incidence of infection in the endogenous population, and a reasonable rate of infection, so that the trial can be conducted in a reasonable time frame. However, even under the best of circumstances, several thousand volunteers and several years are usually required to accumulate enough data for analysis to show whether the vaccine will work, and how well it works, i.e., whether it confers complete protection from infection, or only partially effective, affording protection for a fraction of recipients compared with the incidence in the placebo control group. Humanity usually panics when faced with any serious problem, disease epidemics included. To worsen matters, we have been confronted, since 1984 with the worst pandemic in history HIV/AIDS, a pandemic that threatens to unravel societies around the world, just at the time that we have all become interdependent in a "global economy". Accordingly, the search for an effective HIV vaccine is perhaps the most important scientific challenge of our generation, if not the most crucial ever in the history of science [3]. Not surprisingly therefore, it has indeed been panic galore all over the world since the isolation of the HIV as

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Safe and Effective HIV Vaccines Since 1999

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the causative agent of AIDS, a situation that has literally paralyzed even normal scientific reasoning, approach and open-mindedness. Alice Park, writing in TIME Magazine’s Edition of March 29, 1999 on AIDS, said, “For the nearly 35 million people around the world now living with HIV, there may never be a cure. Once cells are infected with HIV, it’s excruciatingly difficult - perhaps impossible - to rid them of the virus. The only sure way to stop the epidemic is to prevent infection in the first place and only a vaccine can do that. … As scientists learn more about how HIV co-opts the human body to survive, they are realizing that drugs alone may not be enough. To contain the virus effectively, it may take a balance between drug therapy that keeps HIV levels low and a bolstered immune system that can then target and destroy the remaining virus. Until scientists find a vaccine, however, they may control but never cure the century’s final scourge.”

Unfortunately, neither Alice Park nor any other writer I have come across defines ‘cure of HIV infection’. Later in December 1999, the same TIME International Magazine, described the 20th century as

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‘…the century that split the atom, probed the psyche, spliced genes and cloned a sheep. It invented plastic, radar and the silicon chip. It built aeroplanes, rockets, satellites, televisions, computers and atom bombs. It overthrew our inherited ideas about logic, language, learning, mathematics, economics and even space and time. And behind each of these great ideas, great discoveries and great inventions is, in most cases, one extraordinary human mind.’

Sadly however, this worst pandemic known to man, HIV/AIDS has continued to rampage humanity till now. All told, the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated in June 2000 that sub-Saharan Africa had 15 million deaths from AIDS, 12 million AIDS orphans, and 24.5 million people living with the virus - a whopping 70% of the global AIDS total, even though this region has a mere 10% of the world’s population. ‘Despite millennia of epidemics, war and famine,’ stated UNAIDS, ‘never before in history have death rates of this magnitude been seen among young adults of both sexes and from all walks of life.’ A vaccine, the report concluded, represented ‘our best hope’ of stemming the epidemic, (I agree so far) ‘but it will take time and a concerted international effort before we have one.’[4]. UNAIDS did not produce any data, control trials or any scientific work, even if haphazard, shoddy or wishy-washy to support its assertion that it ‘will take time and a concerted international effort before we have one’ HIV vaccine. Since this assertion by UNAIDS has no scintilla of scientific foundation, would one not be justified to discard it as spurious? This chapter critically looks at the attempts by others since 1984 to develop safe and effective HIV vaccines and what, in the author’s opinion, are responsible for the persistent failure. The chapter also looks at the author’s single-handed efforts in Nigeria, a developing country in sub-Saharan Africa, at developing safe and effective HIV vaccines, the results he has achieved, some of the events that have followed his effort, and token examples of the dividends that have been his lot for his effort or effrontery. The first scientific publication of

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Jeremiah O. A. Abalaka

4

the author’s work was a report in 2004 that was preceded by an editorial which said, inter alia, “… Additionally, he has provided this author with a detailed account of the process he uses so that I am able to assure readers that to the best of my understanding the method he deployed is at least a plausible approach to a vaccine. …. While Abalaka did everything in his power to make sure that these gave reliable indications of blood parameters following treatment/vaccination, it is always possible that such data may be fabricated. My assessment of this situation is that the data are as real as they can be. … Abalaka noted that the antibodies for both HIV and Hepatitis C virus as well as Hepatitis B surface antigen changed from positive to negative levels following the treatment/vaccination procedure. … In any case these data are remarkable as they fly in the face of current concepts of immunology. They are presented here to stimulate further checking and investigating … Desperate situations call for desperate measures. I believe that Abalaka has risen to this challenge. I also hold that within the limitations of his situation he has sought with diligence and conscientiousness to faithfully record the evidence as it appears to him; warts and all. …” [5].

In spite of this editorial, no scientist, researcher or research institution has taken the initiative at any or ‘further checking or investigating’ since 2004 when the editorial and the accompanying report were published.

SOME PRE-1984 VACCINES FOR HUMAN USE It is really very unfortunate that mankind generally learns little or nothing at all from the lessons of history. Even though I am not a historian, I recognize that history contains a wealth of knowledge that helps us to better understand and handle any similar problems that may face us in our brief sojourn on earth. What then has history to teach us about (some) vaccines since mankind’s existence on this planet?

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Plague We know from the historian Thucydides in the fifth century B.C that people knew then that because survivors of plague were ‘never attacked twice - never at least fatally’, such people were involved in caring for those sick or dying from the disease [6]. Lesson - plague confers natural immunity after an attack.

Variolation Smallpox (variola) is a highly infectious disease that causes severe morbidity (blindness, hearing loss, unsightly and permanent pock scars on the skin especially of the face, etc) with about 30% mortality rate. Like plague, it has been known since antiquity that survivors of smallpox do not get a second attack.

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‘Variolation’, an effort at causing a mild form of smallpox by using dried powdered scabs from those with mild forms of smallpox, was practised by the Chinese in the sixth century A.D. In India, England, the Ottoman Empire and the New World (now USA), variolation was also practised in the eighteenth century A.D. Variolation was eventually outlawed in America and England because some of those variolated died of smallpox [7]. Variolation, though effective, is not safe enough to be used for trying to prevent smallpox. The safety of any disease remedy, vaccines inclusive, is of prime importance.

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Edward Jenner’s Smallpox Vaccine Edward Jenner was born and brought up in Berkeley in the English farming county of Gloucestershire, about 240 kilometres northwest of London. Like others before him, Edward Jenner (1749-1823) knew about the belief among dairy farmers in England in his days that infection by the relatively harmless cowpox (then called ‘Variolae vaccinae’) protected the person against smallpox, but no one had ever tested the belief. While practising as a medical doctor there, he decided to test the extant belief then that cowpox infection protected against smallpox. On May 14, 1796, he took pus from a cowpox lesion on the hand of a milk maid called Sarah Nelms and injected it into the skin of his 8-year old nephew James Phipps. Jenner could not use himself for his experiment because he had been variolated as a schoolboy. The cowpox sores on James Phipps’ skin resolved and disappeared after about 6 weeks. Jenner then injected virulent human smallpox into his nephew’s skin. Lo and behold! James did not develop the disease smallpox. During the next few years, Jenner carried out the same procedure on over 6,000 people. He also repeatedly challenged James Phipps with live wild smallpox. None of them developed smallpox. Even though it was known before Jenner that a person could become resistant to diseases like plague or smallpox, he was the first person to successfully and scientifically conceive, develop and apply a vaccine against a disease. Jenner had no idea about how and why his vaccine worked. In an 1800 paper titled ‘A Continuation of Facts and Observations Relative to the Variolae Vaccinae’ Jenner predicted that his discovery would ‘extirpate smallpox disease that has ever been considered as the severest scourge of the human race’ from the earth [8]. His prediction was indeed fulfilled about 200 years later. The last reported case of smallpox was from Somalia around 1977, and on December 9, 1979, the chief scientists of the WHO declared that smallpox (as a naturally occurring disease) had been eradicated from this planet [9]. The existence of microbes including bacteria and viruses was unknown to humanity at the time of Jenner. Edward Jenner was, by and large, an ordinary doctor with no previous experience in vaccine research, development or production. He did not use either controls or laboratory animals in his work on smallpox (the scourge had been afflicting only human beings i.e., there were no known animal reservoirs of the disease). He did not depend on any knowledge or skills he acquired during his medical training for his smallpox work. He took

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pus from a cowpox lesion on the hand of a milk maid and injected it directly into the skin of another person. I am one of the many that believe Jenner would have used himself instead of his nephew for his experimentation if he had neither been variolated nor suffered smallpox. After about 6 weeks, Jenner injected virulent smallpox virus into his vaccinated nephew, and later on, in all the other vaccinated people to test if his vaccine had offered them protection against the disease. He also repeatedly challenged his nephew with live smallpox. Neither the nephew nor the others developed the disease. Smallpox, before and during Jenner’s time was ‘the severest scourge of the human race’. In other words, Jenner met a desperate situation and took desperate measures to tackle it. His peers neither appreciated nor applauded Jenner for his work; instead they did everything possible to frustrate him. Jenner was later on knighted for his work on smallpox. The world continues to hail him for his brilliant work that has led not only to the control of, but also to the eradication of smallpox. However, had Jenner lived today and done what he did, he would not only have lost his medical license but would have been tried and likely jailed for life, if not executed, for unethical medical practice and crimes against humanity. Since cowpox was known to cause only a mild illness long before Jenner’s time, Jenner did not need to do any trials before testing cowpox on those at risk from smallpox. It was also known before Jenner that cowpox infection protected against smallpox, and as such Jenner did not need any other trials before injecting virulent smallpox into his nephew’s skin - the chap had been successfully infected with cowpox! Jenner’s single-handed, innovative work and discovery eventually led to the eradication of smallpox from the world. Jenner who developed an effective and safe smallpox vaccine was not the person that isolated the causative agent of smallpox. Microbes were unknown to humanity during his time. Jenner did not know how and why his cowpox vaccine worked. Confronted with the smallpox scourge, the only crucial factors are the safety and efficacy of his vaccination, not any trumpeted ethical considerations or how and why the vaccination worked.

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Louis Pasteur’s Vaccines Unlike Jenner, Louis Pasteur (1822-95) was not a medical doctor. He was a great Chemist and a renowned Bacteriologist. The existence of viruses was still unknown to humanity even during Pasteur’s days. It was about 5 years after Pasteur’s death that a scientist postulated the existence of viruses. The momentous discoveries of Louis Pasteur in the second half of the nineteenth century completely revolutionized agriculture, chemistry, medicine (human and veterinary), hygiene, and surgery. Though Pasteur’s discoveries were accepted and applied very quickly by their users (industrialists for pasteurization, farmers for veterinary vaccines against fowl cholera and anthrax, people bitten by rabid animals for his rabies vaccine), they were accepted much later by the scientists (human and veterinary doctors) because they could not explain the mode of action of the vaccines. Surgeons who had been practising for many years without any rules of hygiene would not accept Pasteur’s new rules of hygiene even though they had been infecting most of their patients. Only the English Surgeon Joseph Lister (1827-1912)

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was greatly influenced by Pasteur’s researches, and was the first to introduce antiseptic measures in his surgical practice with very rewarding results. Pasteur was the first person to produce a vaccine (a weakened form of fowl cholera bacilli) in the laboratory even though he knew little about the mechanism by which the bacilli killed fowls. Later, Pasteur produced in his laboratory effective human rabies vaccines using weakened and killed rabies virus obtained in slices of the spinal cord of rabbits suffering from rabies. It had been known even before Pasteur’s days that rabies was a uniformly fatal disease. With the onset of the symptoms of rabies, the sufferer invariably died agonizingly within the next 10 days. Europe was under siege by rabies at the time of Pasteur. He used the spinal cord of rabid rabbits to prevent people bitten by rabid animals, and were therefore infected with the lethal rabies virus, from developing rabies. The first demonstration of the efficacy of his vaccine was on a lad brought to him for his remedy after a rabid dog bite. The doctors of his days rose in severe opposition, threatening that if the boy died after Pasteur’s treatment, they would kill Pasteur (as if the boy had any chance of survival without Pasteur’s treatment!). Pasteur ignored the ranting of the doctors and treated the boy. The boy never developed rabies. Later, patients bitten by rabid dogs were brought to Pasteur in Paris even from as far away as Russia, a journey of several days then. With Pasteur’s therapy, most of them survived [2]. Viruses were not known to man in Pasteur’s days, yet he single-handedly developed a safe and effective therapeutic vaccine against rabies, a viral infection that is still uniformly fatal in any person who develops clinical signs of the disease. Like Jenner, Pasteur who was not the person that isolated the causative agent of rabies developed a safe and effective vaccine against the disease. The rabies vaccines in use up till today are just modifications of Pasteur’s rabies vaccine. Again the lesson is clear - one need not know how or why a vaccine works provided it works. The opposition from doctors against Pasteur’s vaccines was unjustified. Pasteur rightly ignored them and proceeded, prompted only by his interest in preventing the victims from dying of rabies. Any new discovery receives severe criticism because man is always opposed to change. One should ignore such opposition against new medical remedies that are safe and effective. Ethical considerations, protocols and the how or why a remedy works are irrelevant whenever there is a new but safe and effective remedy against any human epidemic - desperate situations require desperate measures.

Polio Vaccines I have, for illustration, selected the chronological development of polio vaccine in the United States because I have access to accurate information and data about it [10]. The cases quoted are new cases reported in the US. 1894 - Polio killed 18 children in Rutland County, Vermont, and paralyzed 114 others, the largest outbreak in the US at that date. 1899 - Scientists in Vienna showed that polio was spread by an infectious agent. 1908 -Landsteiner isolated the polio virus, but did not develop any safe and effective polio vaccine.

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1911 - After 18 months work on polio virus, Flexner, an American, predicted that within 6 months a remedy would be announced. His prediction was not correct. 1916 - Over 27,000 cases and 7,179 deaths. There was panic in New York where over 2,000 died. (People fled Manhattan, only to meet armed robbers in the suburbs. Some hospitals refused to admit cases for fear of infecting others. Cities impounded cats and dogs because authorities mistakenly thought they could transmit the virus to humans. Parents sealed windows and doors and refused to let their children outside to play. Miracle cures like ox and frog blood, cedar shavings, and radium water abounded.) 1921 - Franklin Delano Roosevelt (1882-1945), the 32nd President (1933-1945) of the US was, at 39, crippled by polio in 1921. 1934 - This year marked the beginning of the personal involvement of President Roosevelt in raising funds for polio victims. He established the President’s Birthday Ball Commission for Infantile Paralysis (polio) that was renamed The Commission for Infantile Paralysis the following year. In 1937, he replaced it with the National Foundation of Infantile Paralysis. 1935 - Maurice Brondie of New York University reported he had protected monkeys with a killed poliovirus vaccine. Using funds he received from the Commission for Infantile Paralysis, he distributed his vaccines to hospitals and health departments. More than 9,000 children received the vaccine. John Kolmer of Temple University claimed about the same time that he had developed attenuated poliovirus vaccine with which, private physicians assisting, he vaccinated about 11,000 kids. It was alleged that some of the vaccinees had developed polio with paralysis, and that some died of the disease. It was concluded that both were ineffective and dangerous. Some suspect that Brodie’s death in 1939 was suicidal even though the official cause of death was coronary infarction. 1938 - 1,705 cases. Working under Thomas Francis Jr. at New York University until 1940, Jonas Edward Salk (1914-1995) acquired experience in isolating influenza virus from mice and inactivating it with ultraviolet light. 1942 - Salk began research on prophylactic viral immunization using the $2,100 fellowship he had obtained from the National Foundation for Infantile Paralysis. 1948 - 27,726 cases. Salk moved to Polio vaccine research. Isabel Morgan of Johns Hopkins University in Baltimore successfully protected monkeys against one type of poliovirus with a killed-virus vaccine. 1949 - 42,033 cases. John Enders, Children’s Hospital, Boston developed the technique of growing polio virus in monkey testicles or kidneys instead of the nervous tissue cultures in use before then. 1950 - 33,000 cases. Salk had developed his own polio virus tissue-culturing system. Hilary Koprowski successfully developed live attenuated polio vaccine by growing the virus in the brains of cotton rats. The vaccine boosted anti-polio virus antibody production. Koprowski and his boss took their vaccines without ill effect. Later, Koprowski vaccinated 20 institutionalized children with his polio vaccine, with their parents’ consent. The children developed antibodies to the virus without illness. Scientists however, still claimed Koprowski had been brash and reckless. 1951 - 28,386 cases

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1952 - With funding from the National Foundation. Salk developed in his laboratory killed (Formalin inactivated) polio vaccine against the 3 strains of the virus, and successfully tested it in monkeys. He was ready for human trials (no ethicists in his University and no FDA in those days). All he needed were willing participants. Salk’s public relations officer had stated publicly that Salk never tested his polio vaccine on himself. However, Salk was reported to have later admitted to a friend that he had actually tested the vaccine on himself. Salk secretly tested the vaccine on a few dozen polio sufferers with their parents’ consent to see if the vaccine boosted antibody production. The vaccine indeed boosted effective antibody production that neutralized the virus in tissue culture. 1953 - 35,592 cases. The National Foundation and the National Institute of Health (NIH) spent $2 million and $72,000 respectively on polio research. Salk announced his achievement on the polio vaccine at a February press conference during which he said scientific publication would follow later. Salk drew the ire of his colleagues for going public before scientific publication. 1954 - 38,476 cases. The National Foundation organized field trials in 44 States when 1,830,000 school children received the (unregistered) Salk vaccine. 20,000 doctors and public health officials, 40,000 registered nurses, 14,000 school principals, 50,000 teachers and 200,000 lay volunteers participated in the field trials. 1955 - 28,985 cases. At a crowded press conference in April, Thomas Francis Jr. announced that from 144 million separate pieces of data collected and analyzed, the Salk vaccine had at least 60% efficacy, and had not caused any significant harm to a single child. The Department of Health, Education and Welfare licensed the vaccine just 2 hours later. The US and the world ‘exploded with joy, dancing and singing and hugging, and blasting, ringing, and clinking anything that would make noise. … During the next few weeks, letters, telegrams, phone calls, and in-the-flesh well-wishers descended on Salk. … There was no end to the awards, honorary degrees, and donations. It was a train of elation, with ever more cars hooking on’. Just 13 days after the Salk vaccine was publicly declared safe and effective, the bubble burst. Unfortunately, Cutter Laboratories of Berkeley, California had accidentally produced the vaccine that contained live virus, causing at least 149 cases of polio out of which 10 died. The Cutter incident, as it was called, frightened many parents away from giving their children Salk vaccine. 1956 - 15,140 cases. 1957 - 5,485 cases. The US Government stopped financing mass immunizations. The USSR started mass vaccination with Sabin vaccine, the oral attenuated polio vaccine. 1958 - 5,787 cases. 1959 - 8,425 cases. 1960 - 3,190 cases. 1961 - 1,312 cases. Licensing one strain at a time, the US Government registered the 1st strain of Sabin vaccine in August. 1962 - In March, the US Government licensed the 3rd strain of Sabin vaccine. In the US now, polio is no longer an important disease. The country has less than 30 cases annually. The following Table summarizes the major milestones of polio vaccine development in the US.

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Some New Yorkers resorted to using frog blood, ox blood or radium water in 1916 when over 2,000 died from polio. With millions of new cases and millions of deaths annually from HIV/AIDS, any effective and safe remedy that will reduce this global burden ought to be embraced, even if it is only 10% efficacious. Then US President Roosevelt, himself a polio victim, was instrumental in raising funds for polio. Almost 2 million children were immunized in the US in 1954 with an unregistered Salk vaccine. The vaccine was only registered the following year after the massive field trial of the previous year showed it was safe and had at least 60% efficacy. The Cutler incident occurred 13 days after this. Table summarizing cases of US cases of polio and the milestones of polio vaccine development

Year

No. of US polio cases

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1911 1916 1938 1948 1949 1950 1951 1952

27,000 1,705 27,726 42,033 33,000 28,386

1953 1954 1955 1956 1957

35,592 38,476 28,985 15,140 5,485

1958 1959 1960 1961 1962

5,787 8,425 3,190 1,312

Total

302,242

Remarks

Flexner, after 18 months work with the poliovirus, said a polio vaccine would be ready in 6 months Panic in New York Morgan protected monkeys using a killed polio vaccine Enders developed monkey testes or kidney tissue culture for poliovirus Koprowski vaccinated 20 children with attenuated polio vaccine Salk's success in monkeys, himself and few dozen children with 3 strains of killed poliovirus Salk announced his polio vaccine success at a press conference 1,830,000 children immunized with Salk vaccine in 44 States Salk vaccine declared safe and was licensed immediately. Cutter incident. US Govt stopped financing mass vaccinations. USSR started mass vaccination with Sabin vaccine.

US Govt licensed the 1st strain of Sabin vaccine US Govt completed licensing Sabin vaccine by licensing the 3rd strain

When it comes to the far worse HIV/AIDS scourge, very unscientific obstacles have been imposed to delay, if not prevent, the development of its vaccines while millions are perishing. Undoubtedly, it was the Salk vaccine, not the Sabin oral vaccine that was responsible for the control of polio in the US. We should also remember that the polio virus was not isolated by either Salk or Sabin. In the interest of the lives of millions around the world affected by HIV/AIDS, we need to radically alter our approach and protocol or ethical posturing. The

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current emphasis, championed by UNAIDS, on ethical considerations, protocol and efficacy trials has resulted in its adherents being guilty of leaving millions to die under the pretext that they must satisfy unethical and unscientific ethical considerations in HIV vaccines development. One wonders if the imposition of these considerations is not a deliberate ploy aimed at depopulating Africa by leaving millions especially in sub-Saharan Africa to die from the HIV/AIDS pandemic; that would be a serious crime against humanity. UNAIDS has no moral, legal or scientific basis for its strange Guidance Document on HIV preventive vaccine research when, as UNAIDS admitted, the vaccine is yet to be developed.

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THE NORMAL HUMAN IMMUNE RESPONSE Though highly complex and still not completely understood, the normal human immune system maintains the integrity and individuality of the person by differentiating between self and nonself. One of the key functions of our immune system is the internal surveillance of our own cells. The normal human immune system develops the ability to distinguish between self and nonself cells as early as around the 8th - 10th week of pregnancy. From then on, the normal human immune system ferociously destroys any cell, tissue or organ that it recognizes as nonself. This is one of the major problems facing tissue or organ transplants. The ferocity with which the normal human immune system destroys nonself cells, tissues or organs is amazing. It takes the normal human immune system just about 10-14 days to completely destroy a large organ like a transplanted but non-compatible liver or kidney from another human being. The ABO, Rhesus and major histocompatibility complex, MHC antigens elicit the most ferocious responses against non-compatible human cells, tissues or organs. As I understand it, cellular immune responses, particularly the cytotoxic T lymphocytes (CTLs), otherwise called CD8+ lymphocytes are responsible for cell, tissue or organ rejection. Another interesting facet of our immune system’s ability to recognize and differentiate self from nonself is the internal surveillance function of our immune system. Even from intrauterine life, the normal human being develops many mutants from the uncountable numbers of mitotic divisions that take place throughout life. As a result of these divisions, many mutants appear. Our normal immune system usually detects or recognizes such abnormal mutants and destroys them. In this way, our internal integrity is maintained. All of us must have developed many potential cancerous cells since we came into existence. Such dangerous mutants however are destroyed by our immune cells carrying out their surveillance function. A person develops cancer when his immune system, for one reason or the other, fails to recognize as nonself the first cancerous cell. Continued growth of the unrecognized cancerous cell eventually leads to the cancerous tumour. Again, as I understand it, cellular immune responses, particularly CTLs are responsible for this surveillance function. Sometimes, for one reason or another, the immune system fails to recognize some cells as self, treats such cells as nonself and destroys them. The autoimmune diseases fall into this category. Our immunological responses are, broadly speaking, either humoral or cellular depending on either the use of plasma/serum (humors) or specific immune cells, even though both responses may occur together to varying degrees depending on the immunogen. Both

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responses are generally highly specific. While humoral immunity depends on the action of highly specific antibodies (gamma globulins), cellular immunity is mediated by direct cell to cell interaction of primed antigen specific T lymphocytes resulting in the destruction of the infected cell. Both types of immune responses, triggered by the extracellular recognition of the immunogen (antigen) by specific receptors on the cell membranes of the immune cells, also involve the secretion and action of soluble factors, cytokines. Both immune responses are extracellular i.e., neither the specific antibodies nor specific effector cells of cell-mediated immunity (CMI) enter the cells during an immune response. Virtually all the vaccines that have been used and/or are being used in humans (such as smallpox, rabies, diphtheria, tetanus, pertussis, polio, measles, chickenpox, mumps, rubella, hepatitis A and B, Haemophilus influenzae B, yellow fever and cholera vaccines) generate, or boost the production of large amounts of effective antibodies against the causative organisms or their exotoxins, as the case may be. Dating back to several decades ago therefore, humanity has always regarded the presence of antibodies against disease-causing microbes in a person’s blood as very good prognostic news because it implies the person has some protection at least against the microbe concerned. This is still not only generally true but it is apparently endorsed by nature! Full-term neonates, in particular, are born with substantial quantities of maternal IgG antibodies that pass across the placenta to the offspring during the last 4 weeks of pregnancy. Maternal antibodies in colostrum and in breast milk also pass to the offspring. These maternal antibodies protect the offspring during the months after birth. The normal child completely catabolizes them before 18 months of age. Premature neonates born before the commencement of the ninth month of pregnancy have a hell of a time battling for survival against various infections because they were unlucky not to stay long enough in their mothers’ wombs to passively receive their mothers IgG antibodies before birth. Because such premature infants have not developed their sucking mechanism fully before birth, they are also unable without assistance to take in their mothers’ colostrum from which they would have received some maternal IgG antibodies. The more premature a baby is, the greater the danger posed to it by the lack or paucity of its mother’s protective IgG antibodies. Accordingly, to imitate nature so to say, passive immunity using immunoglobulins is used clinically to prevent, delay or reduce the severity of some infections in exposed or highrisk cases, for example, globulin administration for hepatitis B, and the use of human rabies immunoglobulin (HRIG), collected from immunized persons and given as soon as possible after rabies exposure especially rabid animal bites on the head and neck. In those people that, for various reasons, cannot produce enough endogenous immunoglobulins, there is also the widespread intravenous use of human immunoglobulins especially in the developed countries, usually by weekly outpatient self-administration in a hospital’s premises. Subconsciously therefore, we are all used to thinking of antimicrobial antibodies as not only beneficial but also inherently indispensable in protection against the diseases they cause. However, there are likely to be exceptions just like other generalizations.

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THE WORST PANDEMIC IN HISTORY, HIV/AIDS The data on HIV/AIDS infection are frightening indeed. Cohen [10] writes thus:

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“More than one in every three adults who live in Botswana or Zimbabwe is infected with HIV. Let that number sink in: 35.8% of the schoolteachers, doctors, cement mixers, mothers, engineers, truck drivers, seamstresses, and politicians are infected with a lethal virus that, in most cases, will cut their lives short by decades. Lesotho, Namibia, South Africa, Swaziland, Zambia, and Zimbabwe are only slightly better off, where the number is one in five adults. In five other countries in sub-Saharan Africa, it is more than one in ten. All told, sub-Saharan Africa now accounts for two-thirds of the estimated 40 million HIV-infected people in the world, and AIDS on that continent is the leading cause of death for adults. Hundreds of thousands of children are infected, and even more have been orphaned. Life expectancy, which steadily had been climbing during the past several decades, is rapidly declining: In Botswana, for example, the World Health Organization (WHO) says the average child born today will live to be about 40; the same child could have expected to live to 70 in the absence of HIV”.

While HIV crumbles sub-Saharan Africa, shaking it like an earthquake that will not stop, Americans largely have lost interest in AIDS. With the advent of powerful cocktails of antiHIV drugs in the late 1990’s, journalists began trumpeting the idea that AIDS was history, which the American public readily accepted. Death rates from AIDS plummeted for a time, furthering the notion that the epidemic has abated and will soon disappear altogether. AIDS activists, politically savvy and effective rabble-rousers who for a decade drew attention to the disease and sped development of treatments, have become as anachronistic as hippies. Most of the world cannot afford the wonder drugs that have staved off disease and death for infected people in wealthier countries. And even in the United States, the advances celebrated a few short years ago are slipping, in no small part because the virus eventually develops resistance to every drug thrown at it. Look at AIDS deaths alone. In 1997, the year after the advent of the powerful drug cocktails, the U.S. death rate from AIDS plunged by 42%. The next year, the drop was only 20%, and the number of new AIDS cases had also nearly doubled from 1997. This is, in short, no time for any country to let down its guard against HIV, especially the United States, which spends more money on AIDS research than all other countries combined. There are many ways to slow the spread of HIV. Using condoms and clean needles, abstaining from sex, treating other sexually transmitted diseases, male circumcision, and screening blood products all have proved effective - to a point. But the best hope the world has to thwart this virus is the same weapon effectively used against smallpox, polio, hepatitis B, rabies, and other devastating viruses: a vaccine. Much effort indeed has gone into finding an AIDS vaccine, and the scientific problems are staggering. Yet there are problems that supercede science. This book describes in detail how scientists came to the impasse they are facing, explaining plainly the complicated mixture of scientific, business, political, and ethical forces that haphazardly steer the enterprise. I also offer a solution to the nonscientific problems that, I believe, ultimately would speed the search for a vaccine, possibly shaving years off the time it takes to slow

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HIV. My proposal is neither revolutionary nor unique: I argue that scientists should approach the problem in a logical, stepwise fashion, testing vaccines in meaningful animal experiments and following up on all promising leads. This book documents how, amazingly, this has not happened to date, and shows the strong forces in the U.S. scientific culture that resist such an approach. And I am convinced that similar problems dog the search for vaccines against malaria, tuberculosis, and hepatitis C-and will hamper vaccine research for new diseases that in the future will suddenly assault populations the way AIDS did in the 1980’s. I doubt that my book, which I began researching in 1989 and completed with help from a Sloan Foundation grant, will single-handedly change the U.S. scientific culture. But maybe, when the public and scientists alike take a careful look at the shortcomings of the AIDS vaccine research effort, a momentum will build to attack the problem with all of the might the world can muster. If one in four adults in the United States were infected by HIV, I am confident that such a critical rethinking of the scientific community’s battle plan already would have happened.” It is not just the loss of interest in HIV/AIDS by the Americans. The US and other developed countries may be more concerned with protecting the huge investments they have made in antiretroviral drugs (ARVs) than in genuinely researching for HIV vaccines. They call the toxic and costly ARVs ‘wonder drugs’ even though these drugs do not cure HIV/AIDS. In 1916, when there were 27,000 cases of polio in the US with 7,179 deaths, there was national panic and fear. In New York where over 2,000 died from the disease, some people went as far as using ox blood, frog blood and radium water for remedy! Safe and effective HIV vaccines have been developed since 1999 from human blood but the Nigerian Embassies of some developed countries [Appendices 1-5] as well as the UN [Appendices 2224] and the WHO [Appendices 6, 22] have ganged up to suppress the development. Why? Is it because they would rather want their home countries to sell off their stockpile of ARVs that were produced at a cost of hundreds of billions of dollars to last for at least 10 years on the prediction of their own scientists that HIV vaccines are at least a decade away. Some have suggested, and they may be correct, that the West just wants to leave HIV/AIDS to do the hatchet job of depopulating Africa so as to create depopulated territories for their citizens to occupy. It seems that the developed world in particular has (deliberately?) become so impervious to reason that it would not even consider the possibility of safe and effective HIV vaccines being developed elsewhere. Then US President, Bill Clinton in his Commencement address at Morgan State University in Baltimore, Maryland on May 18, 1997 declared: “...science is about more than material wealth or the acquisition of knowledge. Fundamentally, it is about our dreams. America is a nation always becoming, always defined by the great goals we set, the great dreams we dream. We are restless, questing people. We have always believed, with President Thomas Jefferson that “freedom is the first born daughter of science.” With that belief and with willpower, resources and great national effort, we have always reached our far horizons and set out for new ones. … Today let us look within and step up to the challenge of our time, a challenge with consequences far more immediate for the life and death of millions around the world. AIDS will soon overtake tuberculosis and malaria as the leading infectious killer in the

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world. More than 29 million people have been infected, 3 million in the last year alone, 95 percent of them in the poorest parts of our globe. Here at home, we are grateful that new and effective anti-HIV strategies are available and bringing longer and better lives to those who are infected, but we dare not be complacent. HIV is capable of mutating and becoming resistant to therapies, and could well become even more dangerous. Only a truly effective, preventive HIV vaccine can limit and eventually eliminate the threat of AIDS. This year’s budget contains increased funding of a third over two years ago to search for this vaccine. In the first four years, we have increased funding for AIDS research, prevention, and care by 50 percent, but it is not enough. So let us today set a new national goal for science in the age of biology. Today, let us commit ourselves to developing an AIDS vaccine within the next decade. (Applause) There are no guarantees. It will take energy and focus and demand great effort from our greatest minds. But with the strides of recent years it is no longer a question of whether we can develop an AIDS vaccine, it is simply a question of when. And it cannot come a day too soon. If America commits to find an AIDS vaccine and we enlist others in our cause, we will do it. I am prepared to do all I can to make it happen. Our scientists at the National Institutes of Health and our research universities have been at the forefront of this battle. Today, I’m pleased to announce the National Institutes of Health will establish a new AIDS vaccine research center dedicated to this crusade. And next month at the Summit of the Industrialized Nations in Denver, I will enlist other nations to join us in a worldwide effort to find a vaccine to stop one of the world’s greatest killers. We will challenge America’s pharmaceutical industry, which leads the world in innovative research and development, to work with us and to make the successful development of an AIDS vaccine part of its basic mission. My fellow Americans, if the 21st century is to be the century of biology, let us make an AIDS vaccine its first great triumph. (Applause)” [10]

The message from President Clinton in 1997 was very clear. He said the American pharmaceutical industry leads the world in innovative research and development, and therefore should be the first (not necessarily, in my view) to develop an AIDS vaccine! He said that America should commit itself to developing an AIDS vaccine by 2007, a decade from 1997. 2007 is here and the US is yet to produce an AIDS vaccine. Meanwhile, some developed countries like the US, France and Great Britain as well as the UN and its institutions such as the WHO and UNAIDS have continued to actively suppress the news of the development of safe and effective HIV vaccines since 1999 despite the scientific publications of the work in international Journals [5,36,37,44,47,49,50]! In all probability, their HIV vaccine ‘experts’, developers, scientists and researchers would certainly have read the publications of our work! Only HIV vaccines developed by them in compliance with their guidelines interest them! One wonders if the millions that have been dying annually of HIV/AIDS ever bothers them at all. If some Americans used frog blood, ox blood and radium water as remedy for polio when faced with a polio epidemic that killed over 2,000 in New York in 1916, why should any American think consider it wrong, scientifically, ethically or otherwise, when pure human blood extract is used as remedy for HIV in an era where human blood and its various components continue to be used for various other conditions in the US and elsewhere in the world.

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When we are discussing safe and effective HIV vaccines therefore, let us always remember that: 1. As long as they are safe and effective, we should not stop or suppress them just because we don’t know how and why they work. 2. A mediocre vaccine today would prevent more infections and death than a terrific vaccine introduced five years later. 3. Insistence on understanding the scientific basics and basis for the vaccine is likely to be a scam, an excuse for not finding out whether it works. 4. The measurable end-point for HIV vaccine development should be a vaccine product, not the number of publications in scientific journals. 5. There will always be those that oppose any scientific advancement, those who want to keep things as they are - to do more research or just wait and see. This is especially inappropriate, if not criminal, at this time with this disease and the vaccine against it. 6. The human immune response is far more complex than can be determined by laboratory tests. It may be sheer scientific arrogance for any one to claim he understands protective immunity. 7. Research is definitely needed but the HIV/AIDS scourge is so devastating that what humanity, especially those afflicted by the disease and those at risk of acquiring the infection, has needed all along are safe and effective vaccines first and foremost. Understanding how such vaccines work comes later.

The First Announcement of the Isolation of the Causative Agent of AIDS

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On a Monday afternoon April 23, 1984, Margaret Heckler, then US Secretary of Health, Education and Welfare, and a lawyer by profession, announced at a jammed press conference that America’s Robert Gallo of the National Cancer Institute had discovered the virus (then called Human T-cell leukaemia virus type III, HTLV-III) responsible for causing the Acquired Immunodeficiency Syndrome (AIDS). At that press conference, according to Cohen [10], Gallo, who had never made a vaccine against anything, then went on to detail a recipe for an AIDS vaccine that, instead of relying on the entire virus like the traditional live and killed approaches, only called for using a piece of the agent that had been produced with genetic engineering techniques. Just such a hepatitis B vaccine was then being engineered that contained the surface protein, or envelope, of that virus. When it came to AIDS, said Gallo, the same logic would apply. “In my view, you’d vaccinate with the envelope protein of the virus”, said Gallo. “We’ll go to recombinant technology, we are doing that now, and we will produce the protein that way. That protein, I would certainly be willing to take if I were a high-risk person, and I’d do it voluntarily. . . That’s the direction we’re kind of thinking about.”

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Gallo proceeded to predict at that press conference that a vaccine for this dreaded and dreadful affliction would soon be in hand, certainly within two years. Firstly, we now know that the HIV was actually first isolated in 1983 by a team from the Pasteur Institute in France led by Luc Montagnier, and that Gallo's group had simply reisolated the same virus that the French team had sent to them a year earlier. It took three years and the intercession of the French and US Presidents to smooth the ruffled scientific feathers, and work out an out-of-court settlement in which both researchers call themselves co-discoverers of the HIV. Even Donald Francis, who had once given a pint of his own blood to Gallo for an experiment, became Gallo’s arch enemy because of this. “The ethics of science are that you’ve got to build on the shoulders of predecessors,” said Francis. “You’ve got to give credit where credit is due. Here’s a man who’s powerful and receives major funding. This guy violated all the standards of virology I know. I had to watch this man for two years after the press conference [announcing that HIV causes AIDS] never mentioning the French. What ‘I, I, I did.’ ” [10] According to Gallo, modern genetic engineering techniques for vaccine production had become the third method of developing vaccines. Hitherto, viral vaccines were developed in 2 ways: live attenuated or inactivated (killed) whole virus vaccines. The new generation modern vaccines are prepared by this third method that uses just protein(s) from the viral surface proteins (envelope) or even portion(s) of the protein(s). According to protagonists (and they constitute an overwhelming majority) of this modern (third) method of vaccine preparation, its great advantage is that such vaccines can never cause an infection since they are devoid of viral RNA or DNA, the crucial infective substance in viruses. With the dawn of this modern method of vaccine preparation, researchers and scientists like Gallo began referring derogatorily to the first 2 methods as ‘old-fashioned’ or ‘traditional’. The derogation, it should be noted, does not change the fact that most of the vaccines in use even now are still produced with the ‘old-fashioned’ or ‘traditional’ methods, and they are safe and effective. Gallo, it must be acknowledged, is a great researcher and retrovirologist. If he had just recalled history however, he would have restrained himself a little and limited himself to the isolation of the virus because almost all successful viral vaccines in use today were not developed by those that isolated the causative agent. Besides, Gallo narrowed the options to only an HIV preventive vaccine. Without much thought, most people would agree with him on this because the overwhelming majority of vaccines known to medicine are preventive vaccines. Just as Gallo implied at the press conference, it is true that many deny the existence of any therapeutic vaccine; many indeed ridicule the idea. An internationally and WHOrecognized Nigerian Professor of Virology (he is not a medical doctor) was quoted in a Nigerian newspaper article in 2001 thus: “Perhaps Dr. Abalaka was overzealous when he was reported to have also claimed that his vaccine also cures. This is immunology heresy. Vaccines don’t cure, they prevent.” [11]

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One expected a renowned scientist and researcher of Gallo’s status to have kept a more open mind since Gallo knew, or ought to have known that therapeutic vaccines have been in existence in human medical practice for long. In man, rabies vaccine since it was first developed by Pasteur over 100 years ago has remained a therapeutic vaccine when administered to a person bitten by a rabid animal; the person bitten became infected with the virus at the time he was bitten. Also, a therapeutic hepatitis B vaccine is used to abort infections in newborns of mothers who carry that virus. More destructively, Gallo literally ruled out other methods of HIV preventive vaccine development when he announced at his press conference that the ‘same logic’ of using genetic engineering techniques and recombinant technology that utilized the viral envelope protein for vaccine preparation would be employed to develop an HIV preventive vaccine. He underscored that view by declaring that he would voluntarily take such a vaccine if he were a high-risk person. When faced with any viral epidemic or disease, it is, in my view, unscientific to exclude from the very beginning, the use of other known and effective methods for its vaccine development just because the causative agent was identified at a time genetic engineering techniques were being used to develop a hepatitis B vaccine. Still basking in the euphoria and limelight of isolating the HIV, Gallo went further to say that an HIV vaccine would be ready in 2 years! Some would say it was very premature, heady and unscientific for him to have gone that far. As it has turned out, that prediction was very wrong. What Gallo, in 1984, called ‘same logic’ for preparing HIV preventive vaccine has now turned out to be very illogical indeed - so far, no logic has been established between HBV vaccine production using genetic engineering techniques and HIV vaccine production. The HBV is not the HIV! When Gallo stated that he would use the same logic of genetic engineering techniques employing the HIV envelope protein to produce an HIV preventive vaccine, he had willynilly implied that an effective HIV preventive vaccine must result in the production of antiHIV antibodies since protein immunogens (antigens) act mainly by stimulating specific antibody production. Since Gallo’s declaration, virtually all HIV vaccine researchers everywhere in the world have not only continued to hunt for the elusive HIV envelope protein for vaccine preparation, but they have insisted that any promising candidate HIV vaccine must stimulate the production of HIV-neutralizing/binding antibodies in experimental animal models and in human trials. Unfortunately and very surprisingly, these researchers have not noticed that the persistent failure with this approach since 1984 indicates there is a fundamental flaw with the ‘same logic’ approach initiated by Gallo. Worldwide, HIV vaccine researchers have been carried away by Gallo’s idea of developing an HIV preventive vaccine, as if Gallo had received a divine revelation on the matter. Invariably, they are all involved in an unsuccessful race to use modern genetic engineering techniques to develop the vaccine using one or more HIV viral proteins. If that approach is flawed, and it is definitely flawed, recurrent failures would continue to be the dividend. Researchers, as they have done and are still doing without critically looking back, would continue along a blind alley, looking for the elusive protein(s) or part(s) of such protein(s) with which to develop the vaccine. After all, human viral vaccines developed with modern genetic engineering techniques that are in use today are very few compared to those made with ‘old-fashioned’ or ‘traditional’ techniques.

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Using the viral proteins or part of such proteins has another grave consequence - they would likely result in the generation of antibodies against such proteins by the recipient. Anti-HIV antibodies do not protect against HIV and they do not prevent the relentless progression of HIV infection to AIDS and death. Universally, HIV infection is diagnosed through the detection of anti-HIV antibodies in blood. Those immunized with HIV envelope proteins would test positive on screening for HIV antibodies even though they are not HIVinfected. I understand for instance that all Nigerian applicants for US visa are subjected willy-nilly to HIV screening by the US Embassy in Nigeria, and that any applicant that tests positive is denied US visa! Imagine! The US, one of the most vocal countries that preach against any form of discrimination against HIV-infected persons, is deeply involved in discriminating openly, shamelessly and unethically against HIV-infected persons! The screening method used by the Embassy does not differentiate between anti-HIV antibodies resulting from HIV infection and antibodies caused by HIV candidate vaccine trials championed by the same US. This example demonstrates the stigmatization that befalls participants in such vaccine trials. One more point - it is even possible that there are other methods of developing effective and safe HIV vaccines other than the 3 methods recognized by vaccine researchers of our generation! What is the scientific basis for saying or thinking that other methods do not exist? I know of none. There is need, in my view therefore, for HIV vaccine development researchers especially to always keep very open and receptive scientific minds, otherwise all their efforts would indeed continue to be, in the words of the title of Jon Cohen’s book, ‘Shots in the dark: the wayward search for an AIDS vaccine’ [10].

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The Natural History of HIV Infection in Man The human immunodeficiency viruses (HIV-1 and HIV-2) are retroviruses belonging to the lentivirus subfamily. Like all retroviruses, the HIV genome consists of 2 single stranded RNA molecules. The HIV is an enveloped virus. It causes a progressive and relentless loss of immune function that ultimately leads to the opportunistic infections and malignancies that characterize the acquired immunodeficiency syndrome, AIDS. Although there is marked variation in the rate of disease progression, the average time from initial infection with the HIV to the development of AIDS is 10 years (range: 18 moths - 18 years). Therefore, HIV infection in man is verily and generally a very chronic infection. HIV-1 is responsible for the global pandemic. HIV-2 was first isolated in West Africa and is said to be related to the Simian Immunodeficiency retrovirus (SIV). The HIV mutates continuously and extensively - it is estimated that any infected person has 1-100 million mutants of the virus at any point in time. Infection by one HIV strain does not protect against infection by another strain. The HIV targets cells with cluster of differentiation class 4 (CD4) receptors on their cell membrane: the CD4+ T-lymphocytes (T-helper cells), monocytes, macrophages, microglia, dendritic cells and Langerhan’s cells. When it infects a cell, the HIV viral core (RNA, reverse transcriptase RT, integrase, protease and other viral enzymes) enters the cytoplasm of the infected cell as a consequence of a complex and permanent fusion of the viral envelope

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glycoproteins gp120 and gp41 (the numbers refer to the molecular weight in kilodaltons) and the cell membrane after the virus locks on to the CD4+ receptors. Even though reverse transcription actually begins during virus assembly and maturation, it is self limiting within viral particles and is dependent on nucleotide pools and other factors required for DNA synthesis. When the viral genome core enters the cytoplasm in a suitable form, reverse transcription is completed, resulting in a haploid, double-stranded DNA provirus which, with the help of viral integrase becomes covalently integrated into the host cell’s DNA in the cell’s nucleus [12,13]. When a cell infected with the HIV undergoes mitosis, the daughter cells inherit the provirus incorporated in the DNA of the mother cell. This is the basis for such popular sayings among clinicians and HIV researchers like “Once infected with the HIV, one remains infected for life” or “HIV infection is incurable” The integrated provirus may remain latent for a long time in resting infected cells. When the infected cell is activated however, the provirus causes the transcription of viral RNA and other viral enzymes, leading to the synthesis, again in the cytoplasm of the infected cell, of new virions that bud off the infected cell. Such infected cells are eventually destroyed by the synthesis, assembly and budding of new HIV virions. Initial primary HIV infection is usually asymptomatic but quite a number of people experience acute symptoms similar to those of mononucleosis within 2-6 weeks of infection. During this initial phase, the person remains anti-HIV antibody negative (‘diagnostic window period’) but seropositive for protein/peptide p24 antigen with high plasma viral load (the person is therefore highly infective). As expected, the first antibody response (primary response) consists of IgM that is usually undetectable in the first 3 months after infection [14]. The IgG response (secondary response) occurs after the appearance of detectable IgM antibodies. Anti-gp160 and anti-p24 IgG antibodies appear first, followed by anti-gp120 and anti-gp41 IgG antibodies. Antibodies to the viral envelope proteins such as gp120 and gp41 persist for life, but anti-p24 antibodies may diminish to nondetectable levels in late stages of the disease [15]. In early HIV infection when there are no neutralizing antibodies, the virus infects and destroys about 200 million CD4+ lymphocytes per day. Eventually, there is a gradual decline of circulating CD4+ lymphocytes as the disease progresses. Generally and without treatment, the CD4+ lymphocyte count in blood decreases by 40-80 cells per microlitre of blood/year in HIV infection. In AIDS, the virus destroys about 20 billion CD4+ lymphocytes per day. A CD4+ lymphocyte count of fewer than 200 cells per microlitre of blood in those with HIV infection is associated with a high risk of developing opportunistic infections and cancers associated with AIDS [16]. The HIV has genes for gag, pol, env, regulatory (early and late) and virion-associated accessory proteins. These proteins are very immunogenic (antigenic). As clearly demonstrated by the universally used ELISA HIV screening test and the Western Blot used for confirmation of anti-HIV antibodies, a person infected with the HIV produces effective antigen-binding antibodies against, among others, viral p17, p24, p9 and p6 gag proteins, p10, p66/51 and p32 pol proteins, gp120 and gp41 env proteins, p14 tat proteins, p19 rev proteins, p27 nef proteins, p23 vif proteins, p15 vpu proteins, p15 vpr proteins and p16 vpx proteins.

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Antibody detection, assay and characterization are far easier to carry out than tests for CMI. Routine and easily performed tests abound for anti-HIV antibody screening and confirmation, but there are no such cheap, easy and simple tests to assess CMI. Tests to assess CMI are costly, take time and require not only special expertise, training and equipment but the use of appropriate animal models with which to assess it. Furthermore, frozen serum, plasma or other body fluids and even tissue samples can be stored for long periods and readily transported across the world for qualitative and quantitative antibody assays. Cells and tissues for CMI assessment are much more difficult to handle. Blood samples for CD4+ lymphocyte counts, for instance, must not be refrigerated and the test must be carried out within a few hours (< 6 hours) of sampling, otherwise the results would be very unreliable. HIV infection usually elicits strong CMI responses involving CD8+ cytotoxic T-cells. Effector T-cell activity can be detected a few days after viral replication starts in many infections. In vivo, this disappears within a few days of the cessation of viral replication, indicating that individual effector cells have a short half-life [17]. Some memory cytotoxic Tlymphocytes (CTLs) however, may persist for a long time, just like the memory antibody secreting cells. Evidence indicates that cell-mediated immunity may be the predominant mechanism for control of HIV in primary infection and in long-term non-progressors [18-20]. In spite of these immune responses to HIV infection however, the body is unable to clear the virus completely and the infection progresses relentlessly to AIDS and death.

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Ethical Considerations in HIV Preventive Vaccine Research Just consider the following hypothetical scenario about a safe and effective deathpreventing vaccine. The world that has for long been looking for the vaccine admits it has not yet been developed. As a result, some lawyers, activists, social scientists, ethicists, vaccine scientists, epidemiologists, representatives of NGOs, people who have lost loved ones and people working in health policy from 33 countries and others met between 1997 and 1999 in several countries at the instance of the UN to look into the failure to develop effective deathpreventing vaccines in spite of the huge funds that had been spent globally for the research. Meanwhile, death of course continues to kill millions of human beings every year. The goals of the meetings were to: (1) identify and discuss ethical elements specific to development of death-preventing vaccines; (2) reach consensus when possible, and elucidate different positions, when not; (3) progress in ability to address these matters during pending or proposed death-preventing vaccine research. At the end, the UN produces a Guidance Document that seeks to offer guidance emanating from these meetings. The document does not purport to capture the extensive discussion, consensus, and disagreement which occurred at these meetings. Rather it highlights, from UN perspective, some of the critical elements that must be considered in death-preventing vaccine development activities. Incidentally, an individual researcher who had been working quietly on the vaccine in one of the developing countries claimed in 1999 that he had developed such a vaccine but his country and the rest of the world have continued to say they would not consider, investigate or recognize the

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claim because the purported discovery had not followed the guidelines in the UN’s Guidance document. Meanwhile, all those who have been following the UN guidelines have still not developed any safe and effective death-preventing vaccine. I wonder what the readers think about this scenario though hypothetical! Let us now look at the following analogous but real situation. The National Agency for Food and Drug Administration and Control (NAFDAC) is Nigeria’s regulatory authority equivalent to the Food and Drug Administration (FDA) in the US. On May 5, 2000, the Chief Executive Officer of NAFDAC wrote a letter to me about my HIV vaccines. Here is an excerpt from that letter:“I herewith enclose the following documents for your guidance:(a) NAFDAC Guidelines on Drug Registration (b) NAFDAC Guidelines on Vaccine Registration; and (c) Ethical Consideration in HIV Preventive Vaccine Research (UNAIDS, guidance document - March, 2000)”

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The 19-page document ‘c’ attached to his letter is captioned “Ethical Considerations in HIV preventive vaccine research. UNAIDS guidance document. Prepublication version. March 2000”, and has 18 ‘Guidance points’. In the following excerpts from that UNAIDS Guidance Document, I have inserted my comments in italics and in parentheses: “As we enter the third decade of the AIDS pandemic, there still remains no effective HIV preventive vaccine (As elaborated later, this is not true!). As the number of those infected by HIV and dying from AIDS increase dramatically, the need for such a vaccine becomes ever more urgent (The more urgent the vaccine need, the quicker the procedure should be to identify safe and effective vaccines against the pandemic). Several HIV candidate vaccines are at various stages of development. However, the successful development of effective HIV preventive vaccines is likely to require that many different candidate vaccines be studied simultaneously in different populations around the world (How did UNAIDS know this likelihood?). This in turn will require a large international cooperative effort drawing on partners from various health sectors, inter-governmental organisations, government, research institutions, industry, and affected populations. It will also require that these partners be able and willing to address the difficult ethical concerns that arise during the development of HIV vaccines. In an effort to elucidate these ethical concerns, and to create fora where they could be discussed in full by those presently involved in, or considering, HIV vaccine development activities, the UNAIDS Secretariat convened meetings in Geneva (twice), Brazil, Thailand, Uganda and Washington during 1997/1999. These meetings included lawyers, activists, social scientists, ethicists, vaccine scientists, epidemiologists. Representatives of NGOs, people living with HIV/AIDS, and people working in health policy (Too many cooks spoil the broth indeed! I am unaware of any precedent like this one in the history of vaccine development against any human viral disease. This again shows that human beings hardly learn anything from the lessons of history! What formed the basis for the guidelines when no one had yet succeeded in developing effective HIV

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preventive vaccines? How can you produce guidelines on how to achieve any target when no one has yet achieved that target?). In the regional meetings, efforts were made to include people from a number of countries from that particular region. The entire process involved people from a total of 33 countries. The goals were to: (1) identify and discuss ethical elements specific to development of HIV preventive vaccines; (2) reach consensus when possible, and elucidate different positions, when not; (3) progress in ability to address these matters during pending or proposed HIV vaccine research. In the present document, UNAIDS seeks to offer guidance emanating from this process. This document does not purport to capture the extensive discussion, consensus, and disagreement which occurred at these meetings. Rather it highlights, from UNAIDS perspective, some of the critical elements that must be considered in HIV vaccine development activities. … (How scientific or rational is it for anybody to offer guidance under the extant circumstance, accepted by UNAIDS, that no one has yet developed effective HIV preventive vaccine? In any case, there are only 2 crucial or critical elements to be considered in any remedy for any disease, safety and efficacy) It is hoped that this document will be of use to potential research participants, investigators, community members, government representatives, pharmaceutical companies, and ethical and scientific review committees involved in HIV preventive vaccine development. It suggests standards, as well as processes for arriving at standards, and can be used as a frame of reference from which to conduct further discussion at the international, national, and local levels. (Charity begins at home! Why has UNAIDS not used its own Guidelines to produce a safe and effective HIV preventive vaccine up till now? Is that failure not a clear pointer to the worthlessness of the UNAIDS Guidelines?) The global burden of disease and death related to HIV is increasing at a rate unmatched by any other pathogen. For many countries, it is already the leading cause of death. Currently available treatments are inadequate because they do not lead to cure (UNAIDS did not tell us its definition of ‘cure’ of HIV infection), but at best slow the progression of disease (This is not true because the HIV therapeutic vaccine developed by the author has cured some people infected with the HIV. And by ‘cure’ of HIV infection, the author means sustained serodeconversion to HIV antibody negative status as a result of the administration of our HIV therapeutic vaccine). The most effective treatment for slowing HIV-related disease progression, antiretroviral medication is complicated to administer, requires close medical monitoring, is extremely costly, and can cause significant adverse effects (Very untrue! The author’s HIV therapeutic vaccine is not complicated to administer, does not require close medical monitoring, is not costly, does not cause any significant adverse effects, and results in cure of HIV infection). Because of this, antiretroviral medication is not readily available to the vast majority of people affected by HIV/AIDS. These are people living in developing countries and in marginalized communities in developed countries. There is therefore an ethical imperative to seek, as urgently as possible, a globally effective and accessible vaccine, to complement other prevention strategies. Genetically distinct subtypes of HIV have been described, and different HIV subtypes are predominant in different regions and countries. Yet the relevance of these sub-types to potential vaccine-induced protection is not clearly understood. … (What the world

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Jeremiah O. A. Abalaka needs are safe and effective HIV vaccines, not the understanding or relevance of any other thing) Some candidate vaccines may be conceived and manufactured in laboratories of one country (sponsor country or countries), usually in the developed world, and tested in human populations in another country (host country or countries), often from the developing world. … (What is the scientific basis for asserting that only laboratories in the developed world can conceive and manufacture HIV candidate vaccines? None. The UNAIDS document seems to be founded on Robert Gallo’s assertions in 1984 when he announced his lab’s isolation of the HIV as the causative agent of AIDS. The document deals not only with HIV preventive vaccine, it upheld Gallo’s view that only modern genetic engineering techniques would result in an HIV preventive vaccine. This is sheer human and scientific pride emanating from nothing other than the sheer belief that only modern genetic engineering techniques and recombinant technology can be used to conceive and develop candidate HIV vaccines, something the developed countries have been doing for over 20 years now, without success. During this period of over 20 years, well over 20 million have died from the pandemic.) HIV/AIDS is a condition that is both highly feared and stigmatised. This is in large part because it is associated with blood, death, sex, and activities which are often not legally sanctioned, such as commercial sex, men having sex with men, and substance abuse. … Given the global nature of the epidemic, the devastation being wreaked in some countries by it, the fact that vaccine(s) may be the best long term solution by which to control the epidemic, especially in developing countries, and the potentially universal benefits of effective HIV vaccines, there is an ethical imperative for global support to the effort to develop these vaccines. This effort will require intense international collaboration and co-ordination over time, including among countries with scientific expertise and resources, and among countries where candidate vaccines could be tested but whose infrastructure, resource base, and scientific and ethical capacities could be insufficient at present (How did UNAIDS know that global support or intense international collaboration and co-ordination over time is required in the effort to develop these vaccines when UNAIDS admitted that the vaccines have never been produced? I do not know of any vaccine developed in the past for human viral infections that had such requirements). … … HIV vaccine development activities take time, are complex, and require infrastructure, resources and international collaboration … (UNAIDS claims they seek effective HIV vaccines as urgently as possible. Yet, in another breath, it says HIV vaccine development activities take time etc. And there is no scintilla of scientific data to support their assertions that HIV vaccine development activities take time, are complex, and require infrastructure, etc. Very strange, I would say.) As health and research communities build HIV preventive vaccine research programmes, attention needs to be given immediately to how a successful vaccine, and other benefits resulting from the research, will be made readily and affordably available to the communities and countries where such a vaccine is tested, as well as to other communities and countries at high risk for HIV infection. This process of discussion and

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negotiation should start as soon as possible and should be carried on through the course of the research. At a minimum, the parties directly concerned should begin this discussion before the trials commence. This discussion should include representatives from relevant stakeholders in the host country, such as representatives from the executive branch, health ministry, local health authorities, and relevant scientific and ethical groups. It should also include representatives from the communities which participants are drawn, people living with HIV/AIDS, and NGOs representing affected communities. The discussions should include decisions regarding payments, royalties, subsidies, technology and intellectual property, as well as distribution costs, channels and modalities, including vaccination strategies, target populations, and number of doses. Furthermore, the discussion concerning availability and distribution of an effective HIV vaccine should engage international organisations, donor governments and bilateral agencies, representatives from wider affected communities, international and regional NGOs and the private sector. These should not only consider financial assistance regarding making vaccines available, but should also help to build the capacity of host governments and communities to negotiate for and implement distribution plans. … In order to be ethical, clinical trials of vaccines should be based on scientifically valid research protocols, and the scientific questions posed should be vigorously formulated in a research protocol that is capable of providing reliable responses. Valid scientific questions relevant to HIV vaccine development are those that seek: 1. to gain scientific information on the safety, immunogenicity (ability to induce immune responses against HIV) and efficacy (degree of protection) of candidate vaccines 2. to determine immunological correlates or surrogates in order to identify the protective mechanisms and how they can be elicited 3. to compare different candidate vaccines; and 4. to test whether vaccines effective in one population are effective in other populations. Furthermore, the selection of the research population should be based on the fact that its characteristics are relevant to the scientific issues raised; and the results of the research will potentially benefit the selected population. In this sense, the research protocol should: 1. justify the selection of the research population from a scientific point of view 2. outline how the risks undertaken by the participants of that population are balanced by the potential benefits to that population 3. address particular needs of the proposed research population 4. demonstrate how the candidate vaccine being tested is expected to be beneficial to the population in which testing occurs, and 5. establish safeguards for the protection of research participants from potential harm arising from the research. …. Participation in HIV preventive vaccine research may involve physiological, psychological and social risks. …

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Jeremiah O. A. Abalaka Participation, if it becomes publicly known, may also cause stigma and discrimination against the participant if s/he is perceived to be HIV-infected (only if one follows their so-called modern approach, the only approach they recognize). Finally, some people may develop a positive HIV test (because the only vaccines they can conceive stimulate anti-HIV antibody production) after receiving a candidate HIV vaccine (conceived and manufactured using the HIV viral protein/s), even though they are not truly infected with HIV, i.e., a ‘false positive’ HIV test. This may result in the same negative social consequences that exist for those actually HIV-infected (Is this not enough handicap to spur them to consider other approaches that may not have this stigmatizing consequence?)… A vaccine with proven efficacy in preventing infection or disease from HIV does not currently exist (This is deliberate falsehood being propagated by UNAIDS. As shown in Appendix 6, I wrote to inform the WHO of the availability of these vaccines in early 1999 but they bluntly refused to even investigate my claim just because the development was not a product of their stereotyped concept of developing these vaccines). Therefore, the use of a placebo control arm is ethically acceptable in appropriately designed protocols. … HIV preventive vaccine trials require informed consent at a number of stages (This applies only to their chosen concept of HIV vaccine development, a choice that does not recognize the possibility that other approaches to HIV vaccine development exist!) … Reducing the risk of HIV infection throughout the trial among participants is an essential ethical component of HIV preventive vaccine trials. All trial participants should receive comprehensive counselling concerning methods of decreasing the risk of transmission of HIV. This should include the basic principles of safe sexual practice and safe use of injection equipment, as well as education concerning general health and treatment of sexually transmitted infections (STIs). Investigators should provide trial participants appropriate access to condoms, sterile injecting equipment (where legal) and treatment for other STIs. All trial participants should also be counselled prior to enrolling in a clinical trial regarding the potential benefits and risks of post-exposure prophylaxis with antiretroviral medication, and how it can be accessed in the community. … The provision of counselling to reduce risk should be monitored to ensure quality and to minimise the potential conflict of interest between the risk-reduction goals and the vaccine trial’s scientific goals. As new methods of prevention are discovered and validated, these must be added to the preventive methods being offered to trial participants. … Women, including pregnant women, potentially pregnant women and breastfeeding women, should be eligible for enrolment in HIV preventive vaccine trials, both as a matter of equity and as a function of the fact that in many communities throughout the world women are at high risk of HIV infection. Therefore, the safety, immunogenicity, and efficacy of candidate vaccines should be established for women, and for their fetus and breastfed child, where applicable. In these situations, the clinical trials should be designed with the interest of establishing the effects of the candidate vaccine on the health of the woman and the fetus and/or breastfed infant, where applicable. …”

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It seems to me that those who met and came out with the UNAIDS’s Guidance document on HIV preventive vaccine research and development made ethical consideration and protocol their most important priority. I doubt if any of them is a Physician. All Physicians are bound by the Physician’s Oath to which they pledged. The words ‘ethical consideration’ and ‘protocol’ do not appear at all in the Physician’s Oath., The health of the patient will always be the first consideration of all Physicians (and I am one). With the greatest respect but utmost sadness, I submit that the UNAIDS Guidance document has not made the health of the patient, the HIV-infected person, the first consideration. Here are the words of the Physician’s Oath: “I SOLEMNLY PLEDGE to consecrate my life to the service of humanity; I WILL GIVE to my teachers the respect and gratitude which are their due; I WILL PRACTISE my profession with conscience and dignity; THE HEALTH OF MY PATIENT WILL BE my first consideration; I WILL RESPECT the secrets, which are confided in me, even after the patient has died; I WILL MAINTAIN by all means in my power, the honour and the noble traditions of the medical profession; MY COLLEAGUES will be my Brothers; I WILL NOT PERMIT consideration of religion, nationality, race, party politics or social standing to intervene between my duty and my patient; I WILL MAINTAIN the utmost respect for human life from the time of conception; Even under threat, I WILL NOT USE my medical knowledge contrary to the laws of humanity; I MAKE THESE PROMISES solemnly, freely and upon my honour.” (Underlining mine for emphasis)

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THE AUTHOR’S APPROACH TO HIV VACCINES DEVELOPMENT All health professionals and the average or ordinary person in almost all countries know quite a lot these days about HIV/AIDS. Let us bear in mind however that HIV/AIDS was unknown to humanity before the 1980’s . Fortunately or unfortunately, I did not enjoy the privilege of learning anything about HIV/AIDS during my undergraduate and postgraduate medical training just like all the other doctors who completed their undergraduate and postgraduate medical training before 1984. I graduated from the Faculty of Medicine, Ahmadu Bello University, Zaria in Nigeria in June 1972. Resident doctors in my country’s Teaching Hospitals then were offered only 1year renewable contract appointments. After housemanship (internship) at that University’s Teaching Hospital, I took another contract appointment in Pathology, spending 3 months each in Haematology under one Prof. Allan Fleming, Microbiology under one then Dr. Egler, Chemical Pathology under one Prof. Discombe, and Morbid Anatomy under one Prof Edington (I am sorry I have forgotten their first names). I then took another contract appointment for 1 year under the said Prof Edington who told me it was crucial for me to be trained ‘in this new specialty of Immunology because no one would make any substantial progress in any field of Medicine especially Pathology without a good training and

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knowledge of Immunology’. I heeded his advice. He then arranged for me to go and do a Postgraduate Certificate Course in Immunology under Prof. Osunkoya (Again, I am sorry I have forgotten his first name) at the University of Ibadan College Hospital, about 600 km away from Zaria. While at that course, Prof Edington arranged for me to attend a WHOsponsored Conference on the Immunopathology of Schistosomiasis in Geneva, Switzerland. I thoroughly enjoyed every aspect of the training in Immunology that I had received. I shifted to Surgery later. After my surgical Fellowship in 1979, I continued clinical surgical practice. Of course, I remain extremely grateful to all my teachers especially during the 3 months rotational attachment in Pathology. In particular, I owe much to Prof. Edington and all who taught me Immunology and its methods.

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A General Surgeon Involved with HIV Vaccines Research and Development? When, in 1984, it was announced that the HIV had been identified as the causative agent of AIDS and its transmission routes were also made public, many African countries including my country claimed they were not affected. In 1986, a Paediatrician Prof. Ransome-Kuti, then Nigeria’s Health Minister announced that HIV/AIDS indeed existed in Nigeria. Public campaigns were mounted to enlighten the public. As a practising general surgeon involved in emergency and elective surgical operations, I had reason to worry. HIV screening tests were not available in those days where I practised, so I had no idea whether any of my patients was infected with the “dreaded and incurable” virus. And yet, I continuously faced the hazard of needle pricks during operations, like any other surgeon anywhere in the world. By 1991 when it had become clear that HIV/AIDS was common in my country, it became even more urgent for me to be protected against HIV if I was to continue surgical practice and keep my dignity - the disease was, and is still highly stigmatized everywhere, my country inclusive. But there was no vaccine against the deadly and incurable HIV infection. The alternative was for me to leave surgical practice and do something else for a living. That option had its serious problems. How would I look after my aged parents and my own family while training for another career? And who would be responsible financially for my training in whatever new career I decided to choose? After using 1991 to examine my options realistically, I took the decision at the beginning of 1992 to face the challenge by falling back on my knowledge of, and training in Immunology to try and develop a preventive HIV vaccine for myself. After all, I reasoned, it could indeed turn out to be a good hobby in the open field of HIV infection that the world had declared ‘incurable’. In my reasoning then, all the leading vaccine developers in the world were ‘rookies’ as far as HIV vaccines are concerned. I might as well join them as another ‘rookie’. What would I lose if I tried and failed? I would lose nothing other than the fact that I had tried and failed, and in that, instead of being alone, I would be one in a large company of many others that had been failing worldwide. Besides, my father had inculcated in me from a very early age that in matters like this, it is far more honourable and rewarding to try one’s hands and fail than to just sit, do nothing and possibly end up a victim of the problem. ‘Come on then, are all men not born equal?’ I told myself. ‘Join the others

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elsewhere in the world that are trying to find HIV vaccines. They are humans like you. With regards to this problem of HIV vaccines, they do not have any monopoly of knowledge and more importantly, they are rookies like you.’ That’s how I joined the club of rookies looking for HIV vaccines. I did not know then, and still do not know of anyone or institution in my country that was, or is involved in HIV vaccines research or development. Everyone in my country was, and is still waiting for an announcement of the successful development of HIV vaccines from the developed world. After all, all other human technological developments including modern medical remedies came to us from there. I would be regarded as insane in my country if it became known that I was trying my hands at HIV vaccine development within the shores of my country. Only a mad indigenous Nigerian living in Nigeria would try such a thing when the ‘white man’ had been trying without success. My idea was taboo indeed. I was not going to have any financial support from anywhere. I remained adamant. I would be on my own! For a start, in early 1992, I began to educate myself as fast and as much as possible on this new disease, HIV/AIDS. By mid-1992, I had learned some basic facts about HIV/AIDS, to wit, The HIV is an enveloped RNA virus unaffected by freezing but inactivated (killed) by heat, desiccation, oxidizing agents, formaldehyde etc, reminding me it is like most human pathogenic viruses. Its infective genome includes the reverse transcriptase enzyme for transcribing a DNA template from its RNA when its infective genome enters the cell’s cytoplasm. The viral DNA template so produced is permanently incorporated into the host cell’s DNA as the provirus. The HIV targets, infects and destroys CD4 helper T-lymphocytes, resulting in acquired immune deficiency syndrome (AIDS) after several years. The virus mutates very rapidly and extensively. HIV infection progresses relentlessly to AIDS and death; it is incurable. HIV infection is diagnosed by confirming the presence of antibodies against various HIV viral proteins in a person’s blood, reminding me that this indirect method of diagnosing HIV not only confirms that the virus is immunogenic but differs very significantly from other viral infections where antibodies are protective. It takes about 2-3 months for an infected person to produce detectable anti-HIV IgG antibodies in the blood. After infection, it takes, on the average, about 10 years for AIDS to develop. In other words, the HIV is very unlike most human viral infections that cause acute infections. Man is the only known natural host of the virus, reminding me of smallpox. Laboratory cultures of the virus are available in the developed countries. Its routes of transmission are through blood-to-blood contact, coitus, the placenta from mother to offspring, and breast feeding. Tests to detect the virus directly are costly and difficult to perform. Attempts at producing a vaccine using inactivated virus and modern genetic engineering techniques had been unsuccessful so far. Antiretroviral drugs were being introduced in the developed countries to try and reduce the progression of the disease to AIDS but such drugs were costly, toxic and noncurative. Armed with these facts, I felt in June 1992 that time had come for me to start tackling my secret, self-assigned and daunting task of trying to conceive and develop, for my personal

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protection, a safe and effective HIV preventive vaccine. While engaged in that assignment, I would continue learning about HIV/AIDS from all possible sources within my reach so as to continuously modify my approach in the light of new facts about or related to my assignment. I had embarked on a very difficult assignment indeed. I had, and still have no training or experience in any vaccine development, no experience in virology, no access to HIV viral cultures or any other viral cultures for that matter, and no training in, experience of or facilities for modern genetic engineering techniques or recombinant technology. In addition, I had no funding. All the same, I had no alternative but to continue to encourage myself by reminding myself that because those without these handicaps had not succeeded, I had at least a chance, even if infinitesimal, of success even with the handicaps. In 1992, my country had neither internet nor GSM communication facilities. Accordingly, I had very limited access to medical literature and current developments on HIV and its vaccine development efforts elsewhere. On the other hand, I considered myself very lucky to even know the few facts I had known about the causative agent. I recalled that other people such as Edward Jenner and Louis Pasteur who developed effective human viral vaccines in the past were not as lucky. I would proceed but how? What is Cure of HIV Infection?

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The world has been bombarded with the slogan ‘HIV infection is incurable’ but there is no matching slogan telling us the definition of ‘incurable’, ‘curable’ or even ‘cure’. According to the aforementioned UNAIDS guidance document, ‘currently available treatments (for HIV infection) are inadequate because they do not lead to cure’. Unfortunately also, the document did not define ‘cure’. And as we all know, many English words have more than one meaning. What then does one mean by ‘cure’ of HIV infection? An English Dictionary [21] defines ‘cure’ thus: ‘To make somebody healthy again. To treat an illness, etc successfully’ Another English Dictionary [22] defines ‘cure’ in these words: ‘A method or course of remedial treatment, as for disease. Successful remedial treatment; restoration to health. A means of healing or restoring to health; remedy.’ A Medical Dictionary [23] defines ‘cure’ as ‘the course of treatment of any disease, or of a special case. The successful treatment of a disease or wound. A system of treating diseases. A medicine effective in treating a disease.’ Regarding ‘cure of HIV infection, I was, and am still not satisfied with any of the above definitions. And I have not been able to see or clearly infer the definition of ‘cure’ for HIV infection wherever I have come across the term. I think it is essential that we all agree on the definition of cure of HIV infection in the interest of uniformity. Since I am unaware of any universal definition of ‘cure of HIV infection’, I suggest that its meaning should be intimately related to how we diagnose HIV infection. The universally accepted method of diagnosing HIV infection is by the screening for, and/or the confirmation of the presence of anti-HIV antibodies in the blood. Accordingly, in my opinion, ‘cure’ of HIV infection ought conversely to be the serodeconversion to anti-HIV antibody negative status in a person

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previously seropositive for such antibodies. And this has always been my working definition of ‘cure’ of HIV infection. If it is indeed true, as researchers have told us, that antibodies to the HIV viral envelope proteins such as gp120 and gp41 persist for life [15], then any treatment that results in the elimination of anti-gp120 and anti-gp41 antibodies in a person previously confirmed positive for these antibodies is effective therapeutically and has resulted in cure of the infection. It is easy to test for anti-gp120 and anti gp41 antibodies since most screening tests for HIV as well as the Western Blot detect these antibodies. In other words, it should be easy, convenient and cheap to confirm or refute the efficacy of any therapy that claims ‘cure’ for HIV infection. Is there any need for controls if one is assessing a therapeutic HIV vaccine for efficacy in man? In my opinion, there is absolutely no need. Others have established worldwide that HIV infection is incurable and that it progresses relentlessly to AIDS and death. Therefore, anyone who conceives a candidate HIV therapeutic vaccine has actually only one river to cross before human trials; he must establish the safety of his candidate vaccine. Once the safety of the vaccine is established, the researcher only needs to test for the efficacy of the vaccine in willing HIV-infected patients on their written and informed consent. There would be no need for controls. The infection is incurable. If the safe candidate vaccine cures even one person of HIV infection, it would be a remarkable achievement since the disease would no longer be tagged ‘incurable’. An analogy may make this point clearer. A person’s death is irreversible. If someone claims he has discovered a therapy that brings the dead back to life, we should just give him corpses to treat. If any of the corpses wakes up and continues his/her life as a human being, the person has confirmed his claim. There would be no need at all for any controls. Only 2 factors are crucial to everyone including the physician and the patient when we are dealing with any remedy for human diseases - safety and efficacy. A safe candidate remedy for an incurable pandemic like HIV/AIDS automatically qualifies for efficacy trials in man, and there would not be any need for controls or meeting any imposed ethical considerations at all since it is safe. Any drug, vaccine or remedy that is both safe and efficacious qualifies automatically for clinical use even if such a remedy has not followed any laid down procedure or protocol, even if no one understands or knows how it works, even if there are no preceding scientific publications by the researcher on the remedy involved. In other words, when it comes to a candidate therapeutic remedy for a deadly and incurable pandemic like HIVAIDS, protocols, ethical considerations and scientific publications take the back seat since they exist just to ensure that the remedy is safe when administered to HIVinfected persons. Therefore they become irrelevant and unnecessary if the safety of the candidate remedy is established beyond reasonable doubt.

The Stepping Stone for HIV Preventive Vaccines Development Was there any thing in the chronicity of HIV infection that I could capitalize on to help me in my assignment? Yes. Eventually, I realized that common sense dictates I should start by trying to develop an HIV therapeutic vaccine first, unlike what is done for other human

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viral diseases that are almost invariably acute infections. With an average incubation period of 10 years for HIV infection to develop into AIDS, I was elated indeed to see that there was actually ample time to try and develop a safe candidate therapeutic vaccine for use in those already infected, and to test the efficacy of such a vaccine on such people. Instead of trying to develop a preventive vaccine for myself, I had to alter my priorities and tackle the therapeutic vaccine first. If I succeeded in developing such a vaccine, I was optimistic that I would then be just a stone’s throw away from getting the preventive vaccine that I needed. I felt that if I took this full sea tide, so to say, it might lead me to my target but if I missed it, I might also miss my target. “There is a tide in the affairs of men Which, taken at the floods, leads on to fortune; Omitted, all the voyage of their life Is bound in shallows and in miseries. On such a full sea are we now afloat; And we must take the current when it serves, Or lose our ventures.” [24]

I believed, and still believe that the key of optimism for my HIV preventive vaccine research effort was that the chronicity of HIV infection can be cheaply and effectively harnessed for the development of safe and effective HIV therapeutic vaccines. The handicaps that bothered me initially - no experience in virology, no training or experience in any vaccine development, no access to HIV viral cultures or any other viral cultures for that matter, no training in, experience of or facilities for modern genetic engineering techniques and recombinant technology, no animal models with which to experiment, and no funds suddenly vaporized into irrelevance and insignificance. This prodded me to proceed with much joy, optimism, satisfaction and enthusiasm.

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Not all Medical Remedies Require Registration before use on Patients As a clinician, I know very well that generally, all drugs and vaccines we use in human medical practice must be registered with a country’s drug regulatory authority such as the FDA in the US and NAFDAC in Nigeria before such drugs and/or vaccines are used. I also know that the manufacture and the application for the registration of drugs falls within the professional responsibilities of pharmacists while the production and the application for the registration of vaccines are some of the responsibilities of vaccinologists, medical laboratory scientists and virologists. Of course, I also know that medical practitioners are not trained at all to manufacture or produce drugs and vaccines; rather, they are trained to use them on their patients through prescriptions. Even if I succeeded in developing a therapeutic HIV vaccine, how was I going to get it registered with my country’s NAFDAC, the regulatory agency for the registration of drugs, foods and vaccines in my country? Happily, I also know fully well as a clinician that some remedies we administer to patients in modern orthodox medical practice are exempt from registration with regulatory agencies like the FDA and NAFDAC. Universally, the transfusion or administration, usually by the intravenous route, of whole human blood and/or its components/extracts does not require registration with any country’s drug regulatory agency. Put simply, it is a private affair involving the donor of the blood, the recipient of the blood or blood product, the

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laboratory that stores the blood/blood product and performs the cross-matching to ensure compatibility if required, and the clinician in charge of the recipient, the patient. Accordingly, whole human blood transfusions and the administration of human blood extracts (packed red cells, plasma, platelets, pooled platelet concentrates, cryoprecipitates, granulocyte transfusions, etc) do not require registration with any country’s drug regulatory agency. Therefore, if only one could successfully conceive an HIV therapeutic vaccine that is just a human blood extract, one would not need to register it with NAFDAC or any other country’s regulatory agency before using it. The safety associated with the administration/transfusion of compatible human blood or its extracts has been established long ago by others, some were long before I went to the medical school. Another albatross had again been taken off my shoulders as I continued on my journey of frontally tackling my assignment. I was in third heaven literally. If one could just develop a candidate HIV therapeutic vaccine that is just a human blood product, one would not need to lose any sleep about its safety especially if it is derived from the infected person’s own blood and is given back to the same person as an autogenous candidate vaccine that is just a human blood product. After all, autogenous whole blood transfusions have been practised for decades without any safety concern e.g., in cases of ruptured spleen, lacerated mesentery or ruptured ectopic pregnancies with massive blood loss undergoing surgery. Of course, such intra-operative autogenous whole blood transfusions are not registered with any regulatory agency at all. ‘Jerry, go on with your assignment that is turning out to be more interesting than you imagined at the beginning. Continue to make the health of your patient your first consideration. Accordingly, make sure you establish beyond reasonable doubt the safety of any candidate vaccine you eventually conceive and develop before you consider efficacy trials in HIV-infected persons. Your candidate vaccine must not make any HIV-infected person worse.’ I told myself.

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Possible Appropriate Immunogens for a Candidate HIV Therapeutic Vaccine Undoubtedly, the HIV is very immunogenic. HIV infection is associated with humoral and cell-mediated immune responses but these are unable to clear the infection. As mentioned earlier, the outpouring of anti-HIV antibodies after HIV infection is massive and extensive. The relentless progression of HIV infection to AIDS and death after, on the average, 10 years after initial HIV infection occurs in spite of these immune responses to the virus. In my view, any HIV vaccines that aim to stimulate anti-HIV antibodies would likely be ineffective just as happens in natural HIV infection. Besides, I still cannot see how such a vaccine would ever cure HIV infection as I earlier explained when dealing with the meaning of cure of HIV infection. Even if such a vaccine were efficacious, how would one confirm such efficacy? How would one differentiate between vaccinated persons and those infected with the HIV when the universal method of screening for HIV infection is by the detection of anti-HIV antibodies in the blood? Recipients of such vaccines would be as stigmatized as those with HIV infection. In a nutshell, I think it is unscientific and naïve to consider developing any candidate HIV

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therapeutic vaccines that involve the production of anti-HIV antibodies. In the light of our present knowledge of the immunopathology of HIV infection, I am better off discarding the possibility of such vaccines. Until we realize that anti-HIV antibodies do not, and cannot provide cure of, or effective protection against HIV infection, we are likely to continue to harvest failure in our attempt to successfully develop safe and effective HIV vaccines. After all, a person already infected with one type or strain of HIV is not protected against infection by another HIV type or strain even though that person already has massive quantities of binding anti-HIV antibodies against various HIV proteins/peptides. The new HIV strain proceeds and successfully establishes itself in the person already infected with the HIV. In other words, the adage, ‘He who is down needs not fear a fall’ does not apply to HIV infection; any HIV-infected person is at risk of picking other strains of HIV infection It is trite immunology that any successful vaccine must contain the appropriate immunogen delivered appropriately. An appropriate immunogen is one that stimulates the necessary appropriate specific immune responses when administered. How was I going to get an immunogen that would tackle all the millions of mutants of the HIV when in any infected person, there are millions of such mutants? Besides that problem, how do I get hold of an immunogen that would eliminate the HIV provirus covalently incorporated in the infected cell’s DNA? This, at first sight, looked really formidable because immune responses take place extracellularly, not intracellularly. Is it possible to think of an immunogen that would eliminate the provirus from its protected and hidden position in the nucleus of the infected cell, a position that very effectively sequestrates it from the host’s immune responses? Unless and until one conceives and develops a vaccine that eliminates the provirus, one would just be wasting his time thinking of getting an effective HIV therapeutic vaccine. It took me several months of intellectual activity before I could lay hold of a possible way of dealing with the provirus menace as well as the extensive mutation of the HIV. I think I should leave interested readers to rattle their brains on this facet of my assignment just as I did. I think it is not only interesting and challenging but it is very possible that by so rattling their brains, some may independently think out better solutions than I did. After several months of further and extensive intellectual exercise and self criticism, I selected a method that I felt might give me an effective immunogen for an autogenous HIV therapeutic vaccine. In processing it into a vaccine, I had to come out with a final product that is just pure human blood product i.e., the only additive to the blood should be the CPD-A anticoagulant used universally in collecting human blood used either for whole blood transfusion or for the preparation of human blood components. Since my candidate HIV therapeutic vaccine would come from the blood of the HIV-infected person, that raw material to be converted into the candidate vaccine naturally contains live and infective HIV. After processing the raw material, it would be necessary for me to inactivate the HIV in the raw material without using chemicals, otherwise I would no longer have a pure human blood extract. If I could achieve these objectives, I would not need to register such a candidate vaccine with any regulatory body before human administration. The only option I had was to free my candidate vaccine of live HIV by using, not any chemical, but one of the already established physical means for HIV inactivation. Further and repeated self-criticisms over several months convinced me that the methodology I had

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conceived ought to be safe. But that was obviously not enough. I had to confirm its presumed safety beyond reasonable doubt. Simultaneously, I had to bear in mind that time was of the essence since many infected persons were dying daily in my country and elsewhere. I therefore decided to use myself for the needed safety confirmation.

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Confirmation of the Safety of the Candidate Autogenous HIV Therapeutic Vaccine Human rabies vaccines are usually therapeutic vaccines given over a period of 14-30 days (depending on the type of vaccine one is using) to persons bitten by rabid or suspected rabid animals. I therefore decided that if the method I had chosen eventually reached the stage of testing its efficacy on HIV-infected persons, the dosage regimen would consist of initial daily outpatient injections for 30 days followed by monthly boosters. I began the safety experimentation on myself on January 1, 1996. I took 20 ml of my peripheral venous blood, processed it exactly as I had designed for the candidate therapeutic vaccine I had conceived, and administered the product to myself, using the intradermal, subcutaneous, intramuscular and intravenous routes every time. I continued the daily injections until the end of March 1996. Over that period of 91 days therefore, I had taken a total of 91 ‘doses’ through 364 injections since I used 4 injection routes each day for each dose. The 20 mls of the peripheral blood I took was arbitrarily taken as a ‘dose’. While taking these injections, I watched out for any symptoms or signs of toxicity. I also carried out weekly haematological examinations (full blood count with reticulocyte counts and ESR) and renal and hepatic function tests. I did not observe any evidence of toxicity. For the next 18 months (April 1996 to the end of September 1997), I reduced the injections to once a week but still using the 4 routes every time. During those 18 months, I had taken additional 78 ‘doses’ through 312 injections. I still did not have any evidence of toxicity. I stopped at that point, convinced that the method was indeed very safe for the 91 + 78 i.e., 169 ‘doses’ I had taken continuously over 21 months. If there were to be any toxicity, I expected that such toxicity should have been enhanced or magnified by my taking the 169 doses over the compressed period of just 21 months. If I went ahead and gave the treatment by daily intramuscular injection for the first 30 days to HIV-infected patients followed by monthly boosters, it would take 140 months (11 years and 8 months) for any patient to take the 169 doses I had taken. I felt, and still feel that a new candidate HIV therapeutic vaccine with an established safety for a period of 11 years and 8 months was good enough for HIV infection that takes, on the average, 10 years to progress to AIDS. I was very satisfied that I had a method whose safety I had established beyond reasonable doubt. I was ready to embark on the vaccine’s efficacy trial in willing HIV-infected persons.

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Efficacy Trials of the Safe Candidate HIV Therapeutic Vaccine I started the efficacy trial on willing HIV-infected persons with their informed and written consent in October 1997. Clinically, I was very pleased with the effects of the vaccine on my patients’ health, their well-being, symptoms and signs. There was rapid improvement in the symptoms of many patients within days of commencement of therapy. Weight loss was regained rapidly. Health and vitality were rapidly restored. Skin lesions, which are common in some of our patients with HIV infection, disappeared rapidly with the treatment. Anorexia, oral leukoplakia, vaginal discharge, thrush (oral, oesophageal or vaginal), diarrhoea and hyperpigmentation of fingernails, where present, responded rapidly in many cases to the therapy/vaccinations combined, as necessary, with specific chemotherapeutic agents. ‘Dirty lung’ appearances on chest radiographs responded to the vaccinations with radiological evidence of improvement within a few weeks of therapy. Severe anaemia was treated by blood transfusions that were usually carried out by other clinicians looking after the patient since our therapy was an outpatient procedure. Any other identified and treatable disease was aggressively managed. In many cases also, initial (pre-treatment) blood pictures of abnormal red and white blood cells morphology especially atypical lymphocytes reverted to normal rapidly with therapy while elevated pre-treatment ESR fell drastically with therapy. On December 28, 1998, I recorded 4 cases of serodeconversion to anti-HIV antibody negative status among the persons that had undergone my therapy. Their HIV screening tests were performed in the same laboratory where they had been confirmed HIV seropositive before they started my therapy. My joy was indescribable. Could I indeed be closing in on developing a safe and effective candidate HIV preventive vaccine for myself? What I had been doing secretly for years had then reached a stage where, if I was to make further meaningful progress, I had to try and recruit others especially a reliable and experienced medical laboratory scientist to help me to perform critical laboratory tests as I decided to proceed by systematically collecting more data to confirm or refute these unique results from the therapy. In January 1999, I got such an independent, experienced, meticulous and hardworking medical laboratory scientist to do all the necessary investigations on my patients for me. I have been using his laboratory Peak Medical Laboratories since that time.

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Proceeding to the HIV Preventive Vaccine Of course, it was not possible for me to forget why I involved myself in this whole exercise that had taxed my intellect and drained my family’s finances since 1992 - I needed to protect myself against the rampaging HIV. After I got these 4 cases of serodeconversion to anti-HIV antibody negative status, I decided on March 1, 1999 to take 30 mls of the peripheral venous blood of one of my blood group O+ HIV-infected patients (I am also O+) who had not started the therapeutic remedy, and used it to prepare my first candidate HIV preventive vaccine using slight modifications of the method I used to prepare the therapeutic vaccine. I gave that candidate vaccine to myself by deep intramuscular injection immediately. Of course, I had screened the patient and confirmed she was negative for hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) IgG antibodies.

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Three months later, I felt, on general immunological principles that the candidate preventive vaccine I had taken ought to have primed my immune system well enough, if indeed it was efficacious. How was I to know if it had offered me any protection or not? Challenge yourself with wild HIV as Jenner did to his 8-year old nephew James Phipps. I then confidently challenged myself on 1/6/1999 with an intravenous injection of 2 mls of fresh whole untreated O+ blood in CPDA-1 anticoagulant taken from another confirmed HIV-1 infected patient who had not started taking the therapeutic vaccine and who had been screened and found negative for HBsAg and anti-HCV IgG antibodies. (Like most of my HIV-infected patients, the evidence that there was infective HIV in the blood of this patient was the assays that were routinely carried out to make sure that when I made vaccine I used blood from an HIV-infected person. These normally consisted of the ELISA screening test used for HIV antibodies and their confirmation using Western Blot.) My confidence in doing this challenge lay in the safe and effective HIV therapeutic vaccine I had developed; if the candidate HIV preventive vaccine failed, I would resort to the therapeutic vaccine to get rid of the virus before proceeding to try and conceive another type of candidate HIV preventive vaccine. As it turned out though, there was no need for me to do that. Later in 1999, I took 5 more similar intravenous challenges of 2 mls each of fresh untreated HIV-1 infected blood from different O+ blood group patients on 11 August, 10 September, 11 October, 11 November and 10 December. A day before each of these challenges, I carried out HIV antibody screening, p24ag assay, CD4+ count, and FBC tests on my blood. The tests were all negative or normal. Since then, I have been doing these tests frequently on myself at 3-monthly intervals at the latest. All HIV parameters in my blood tested in various laboratories in Nigeria and in London have remained either negative or normal up till today. When I told a senior colleague recently about these challenges, he advised me to be taking yearly boosters of the preventive vaccine in case the protection provided by the preventive vaccine I had developed lasts just 3 to 5 years. Heeding that advice, I now take yearly booster doses of my HIV preventive vaccine. I remain willing and prepared to publicly challenge myself with fresh blood group O HIV-infected blood from any suitable person anytime anywhere to demonstrate that I am protected against the HIV. In addition or in the alternative, I am willing to give my blood samples to any researchers anywhere that are interested in finding out my immune system’s response when challenged with ABO compatible HIV-infected whole human blood in vitro and/or in vivo so that such researchers may proceed and elucidate the mechanism(s) involved. In addition, I will assist such researchers to get in touch with (some of) my HIV-infected patients that have been cured so that such patients may give them their blood samples for the same purposes too.

Modifications to the Initial Vaccines and Dosage Regimen Following the initial successes with our HIV autogenous therapeutic vaccines, we had to work out improvements that would allow us to store the vaccine. We began by taking 20 ml of peripheral venous blood in CPD-A anticoagulant taken from standard blood transfusion

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bags, processing it and giving the product, a human blood product, back to the person as an autogenous vaccine. It was extremely tedious and demanding. The first task was to make the procedure simpler. This we did by taking a bag of blood from those that were fit to do so, extracting our raw material of 40-80 ml for vaccine preparation from the blood bag in a closed system that utilized triple or quadruplicate ‘Terumo’ blood bags, and immediately returning the remaining blood by autotransfusion to the donor, usually within an hour after the blood was collected. In that way, we were able to pool together vaccines made from different patients with ABO and Rhesus ‘D’ antigen concordance so as to provide therapy for those, who for one cogent reason or the other such as pregnancy, could not donate a bag of blood for vaccine preparation. It also allowed us to have some stock of the vaccine that we could give to other interested physicians for independent use on their patients. The vaccines are stored frozen in deep freezers at around minus 250 Celsius in 1 ml aliquots ready for administration. As preservative, we add Gentamycin (less than 0.4mg per ml of vaccine) to the vaccines after preparation and before storage. Public electricity supply is extremely erratic and unreliable in our country up till now. We had to acquire enough generators to give us constant and reliable electricity supply whenever there is power outage. Stored properly in this way, the vaccine has a life span of at least 18 months from the date of production. It is thawed and immediately administered by deep intramuscular injection. We started using 1 ml weekly for the first 4 weeks (5 doses) followed by monthly boosters and found this convenient to most of our patients especially those from distant places. We have also used larger doses at more frequent intervals at the request of those that had no financial problems and in those with AIDS, and found that larger doses more frequently administered, say daily or weekly produce faster results. Accordingly, we now confront our patients with these facts in writing and leave each patient to decide not only the dose to take at any visit but also the frequency. As expected, there has been no significant or serious adverse reaction or side effect to our vaccines. The standard CPD-A bag used to collect human blood for transfusion contains about 63 mls of CPD-A, and is designed for the collection of 450 mls of human blood from a person with normal PCV. We use the PCV to adjust the volume of blood we take from our patients for vaccine preparation so as to improve the quality of the raw material we extract from each bag of blood. In acute and severe whole blood loss as may occur in injuries, obstetric problems or major surgery, a patient may receive several bags of compatible whole blood administered intravenously over a short period of 24-48 hours. The toxicity of a dose (1ml) of our HIV vaccines, a pure human blood extract is therefore 1/450 of the toxicity of one bag of compatible whole human blood transfusion. We ensure there is ABO and Rhesus D antigen concordance during the preparation, storage and administration of our HIV vaccines.

THE VACCINES ON LARGER POPULATIONS We use the CDC classification of A1-A3, B1-B3 and C1-C3 [25,26] for our HIVinfected patients. By this classification, A1, A2, B1 and B2 are non-AIDS HIV infection whereas any C or 3 is categorized as AIDS.

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For emphasis, we have developed HIV, not AIDS, vaccines. In fact, it is literally impossible to have an effective AIDS vaccine since AIDS is a syndrome is characterized by one or more opportunistic problems (infections and/or cancers) against which our HIV therapeutic vaccine has no effect. Like the late, advanced, terminal stages of any disease or infection, AIDS, the late, advanced, terminal stage of HIV infection is also extremely difficult to attempt to cure. Besides, the immunological competence in those with AIDS may not be sufficient to enable such patients benefit from the vaccine therapy. All AIDS cases seen in our hospital are therefore clearly informed about their advanced condition that may deprive them of adequate benefit from our remedy. Despite this caution and explanation, some AIDS patients still opt to take our therapy while their personal physicians look after their opportunistic problems. Such AIDS patients commit their informed preference into writing before starting our therapy. The following Table summarizes the cases of serodeconversion for HIV antibodies, HCV antibodies and HBsAg following our therapeutic HIV vaccine intervention in about 4,300 patients that registered for the vaccine therapy. Some of them registered for the therapy but never came back to start treatment. Many took just a few weekly doses and disappeared. Recently, some have come back after 2-3 years or more to resume their therapy. Of course, some of these patients that registered for our remedy are still undergoing treatment.

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Table summarizing the details of the patients that serodeconverted to negative (normal) for HIV antibodies (ab), HCV ab and HBsAg following treatment with the author's HIV therapeutic vaccine

Serodeconversion to negative (normal) for

No. of cases of serodeconversion

Range of no. of days of treatment with our HIV therapeutic vaccine before serodeconversion

HIV ab HCV ab HBsAg

28 23 71

6 - 498 91 - 559 7 - 445

Mean of days of treatment before serodeconversion

No. of serodeconverters that have come back for follow-up since we discharged them from our Hospital

No. of serodeconverters maintaining serode-conversion on follow-up after we Discharged them from our Hospital

113 188 152

5 3 7

5 3 7

We have found out that quite a number of our HIV patients carry out their own screening tests, and fail to show up (out of the fear of the stigma attached to the infection) as soon as they find they have serodeconverted. In addition, they would prefer not to let anybody know they were previously HIV positive for the same fear of stigmatization and ostracization because everyone says HIV is incurable. An admission of being HIV-positive in the past would attract instant stigma because no one would bother to know the current status of such a person. Our records for those that have serodeconverted of course exclude such patients. It is generally believed and accepted that safe and effective HIV vaccines have been difficult to achieve not only because of the extensive genetic variability of the virus but also

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because of the problem of obtaining the appropriate immunogens delivered appropriately. Accordingly, most candidate HIV vaccine concepts and strategies involve the use of immunogens specific for the predominant subtypes found within a country or geographic region. HIV-1 subtype A, for instance, was reported in 1994 to be predominant in 21 African countries [27], but a more recent survey in our country Nigeria shows a clear dominance and widespread distribution of gp41 subtypes A and G, even though a subtype C and a subtype J were also identified [28]. Available evidence indicates that cell-mediated immunity may be the predominant mechanism for the control of HIV in primary infection and in long-term non-progressors [2934]. HIV envelope subcomponent vaccines have limited ability to induce neutralizing antibody production against clinical HIV-1 isolates [35]. We have applied our HIV therapeutic vaccine to HIV-infected persons not only from all parts of Nigeria, but also from other parts of Africa and other continents. The therapy has therefore been used for various subtypes of HIV-1 infection as well as on just 2 cases of HIV2. The HIV type or subtype in any person receiving our remedy does not appear to affect the efficacy of our HIV therapeutic vaccine. Some of the patients we have treated serodeconverted to HIV antibody negative status after a few weeks or months of the treatment, thereby confirming that detectable humoral responses likely played no role in the vaccine’s efficacy. Such rapid serodeconversion with the therapy occurs consistently in those with recent HIV infection - negative screening for HIV antibodies during the preceding 3-6 months, initially ‘indeterminate’ HIV infection rapidly progressing to established HIV infection by Western Blot, and/or low titres of antiHIV antibodies. The complete catabolism of passively acquired IgG antibodies across the placenta from mother to offspring may take up to 18 months. It may take up to 5 years from the time of complete elimination of the HIV in an HIV-infected person for complete catabolism of his/her own actively-acquired IgG anti-HIV antibodies. Obviously therefore, the rapid serodeconversion within a few weeks/months in some patients is not the result of any catabolism of their own anti-HIV IgG antibodies. In early HIV infection, the body has a large preponderance of normal immunocompetent cells and a relatively small population of HIV-infected cells. In such early infection, we postulate that it takes just a few days after starting the therapy for the body to clear all HIVinfected cells. The selective vaccine-induced recognition and destruction of HIV-infected cells in early HIV infection releases intracellular HIV antigens that are immediately mopped up by forming immune complexes with the small quantities of circulating anti-HIV antibodies present. This would explain the rapid reversion to HIV antibody negative status in those patients with recent HIV infection treated with our remedy. The formation of immune complexes between specific antibodies and the various HIV gp and p fragments takes place continuously during HIV infection. The deposition of similar circulating immune complexes containing HBsAg appears to be a key factor in the pathogenesis of most extra-hepatic manifestations (arthritis, polyarteritis nodosa, erythema nodosum, glomerulonephritis, uveitis, Gullain-Barre syndrome) of acute and chronic hepatitis B infections [34]. We have not yet seen similar manifestations that may be related to the

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deposition of similar complexes in HIV infection or those taking our HIV therapeutic vaccine. There is a consistent but transient rise in serum uric acid during the first few weeks of commencement of our therapy. At the same time, the CD4 count dips before beginning its steady rise to normal. In many patients especially those that have had HIV infection for years before commencing the treatment, the viral load rises in the weeks or months following commencement of therapy. Later, however, the viral load then begins a steady decline until vironegativity occurs. All these seem to be indications of large-scale immunologically induced T-cell destruction of HIV-infected CD4 lymphocytes and other cells. Some HIVinfected patients on our therapy eventually lose their IgG antibodies, serodeconvert to negative and remain healthy with a sustained HIV seronegative status. We therefore postulate that our therapeutic vaccine may be acting by inducing a cell-mediated cytotoxic immune response that involves the selective recognition and destruction of HIV-infected cells. With HIV infections that have lasted longer however, the preponderance of normal immunocompetent cells over HIV-infected cells is reduced, while the amount of circulating HIV antibodies is much higher. We have found that the serum IgG antibody levels in some of those with several months or years of HIV infection that we have seen were higher than normal levels of serum albumin. The foregoing postulate of the mode of action of our therapy would also explain the varying periods of time it takes to achieve seronegativity in the HIVinfected persons undergoing treatment with our remedy. This postulate of the mode of action of our remedy also fits in with the observation that the vaccine does not trigger the production of any detectable anti-HIV antibodies using the ELISA screening test and Western Blot. After our work was published in 2004 [36], Lehner, in a letter to the Editor [37], kindly drew our attention to the possibility that alloimmunity might account for some of the results obtained with our HIV vaccines. He reminded us that 1. Human epidemiological studies had shown that sex workers resistant to HIV-1 infection are more likely to express rare HLA alleles [38]. 2. the transmission of HIV from infected mothers to their offsprings is increased with HLA-1 concordance [39]; 3. HIV replication is inhibited with allogeneic stimulation of T-cells in vitro [40], and 4. Artificial systemic alloimmunization of women [41,42] or natural vaginal alloimmunization during unprotected sex with single partners [43] showed significant in vitro protection of T cells to HIV infection. In our response to Lehner’s letter [44], we admitted that we did not, and still do not know the mode of action of our HIV vaccines, and as such, we admitted that Lehner might be correct to consider that alloimmunity is likely significant in causing the observed effects of our HIV vaccines even though we did not think so. Our reason for not thinking so is based on the fact that we obtained the same efficacious results with autogenous vaccines prepared from and administered to the same HIV-infected person. Keeping an open mind however, we got in touch with Lehner’s group. They agreed, in the first instance, to do anti-HLA antibody studies on serum/plasma samples of those that had

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taken our HIV preventive vaccine. We agreed with their suggestion that we should just label such samples with numbers only and send the frozen samples to them. They bore the expenses for both the transportation of the frozen samples by courier and for the anti-HLA antibody assays. After considerable delay caused by lack of funds for the tests (Appendix 30), they sent the results to us by email on 19 Feb 2007 (Appendix 31). As shown in Appendix 32, Lehner’s group could not ‘make any conclusions either!’ They have suggested that ‘the assay we have used is not appropriate to study your samples and we will have to try the more expensive multiplex assay’. We have requested them to go ahead and we are still waiting for the results. It is possible that cytokines or chemokines may play some role in the mode of action of our remedy. Unfortunately, we have neither the expertise nor the facilities for studying them in the patients so far treated. As far as we know, there is no centre in Nigeria that does such assays. Cell-mediated cytotoxic immune responses are effected, in some cases, by long-lived Tlymphocytes, monocytes and macrophages. Consequently, vaccines that act largely by such responses may offer protection for several years, e.g., the yellow fever vaccine. It is therefore possible that our vaccine, if it acts through cell-mediated cytotoxic immune responses as we postulate, may produce immunity against the HIV, probably for 3-5 years or longer. Followup of healthy patients in particular is a big problem in our country. In this case of a highly stigmatized infection, patients who have serodeconverted disappear literally into thin air because they do not wish anyone to suspect that they ever had HIV infection. Many of them use pseudonyms, fictitious addresses and telephone numbers when they register as patients with us, thereby making it difficult to trace them whenever they disappear. One cannot blame them much when one recalls the widespread and persistent campaign that the infection is incurable. We have been able to follow up a few cured patients for 5 years or more, and they have maintained their HIV antibody negative status. We have started advising them to come for yearly boosters, and we hope they do so. On the basis of the possible mode of action of our remedy, we further postulate that its recipients may pass on, to varying degrees, their cell-mediated protection against the HIV to any recipients of their blood or blood products that contain their primed lymphocytes and to their female sexual partners through such primed lymphocytes in their ejaculates. We have not yet had many cases of HIV-infected pregnant patients that have received our remedy during pregnancy. The 4 cases we have had may be an indication that when given to expectant mothers during pregnancy, the remedy may effectively prevent vertical transmission of HIV from mother to child during pregnancy and delivery. From these few cases, it seems that the offspring of such mothers are adequately protected against the HIV even if breast-fed by their HIV-viropositive mothers provided the mother continues to take the remedy after delivery and during breast-feeding. We routinely give such babies at or soon after birth 3 monthly doses of our HIV preventive vaccine. One of our patients that serodeconverted has had 2 children since serodeconversion even though, against our advice, she had been having regular and unprotected marital affairs with her HIV-positive spouse. Of course, both children are healthy and have remained HIV antibody negative just like their mother.

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Only 2 cases of HIV-2 have received our remedy prepared from HIV-1 infected patients. HIV-1 and HIV-2 genomes exhibit 60% homology in genes that code for core and polymerase proteins and 30-40% homology in genes that code for other viral proteins [45]. One of the 2 patients serodeconverted with the therapeutic vaccine prepared from HIV-1 infected patients. The other patient was doing well on the same therapy but unfortunately has been lost to follow-up. By virtue of the possible mode of action of our vaccine, it is not surprising that the vaccine was also effective against HIV-2. Indeed, the known extensive mutations and diversity of HIV subtypes/clades do not seem to affect the efficacy of our HIV therapeutic vaccine. Globally, hundreds of millions of people are infected with the Hepatitis C virus, HCV. More still are infected with the Hepatitis B virus, HBV. Both are lethal viruses. The latest developments in treating HCV and HBV infections involve the use of antiretrovirals or their distant cousins. A 6-12 month combination of Interferon (an immune booster) and the antiviral Ribavirin is used to manage HCV infection. The 2 drugs combined clear the HCV in just 50 to 55 per cent of patients after 6-12 months treatment. They are very costly and may cause such severe side effects (hair loss and heart failure) that one patient in seven abandons the combination regimen in the United States. Similarly, the antiretroviral AZT is being used for the treatment of HBV infection. AZT too is costly and has severe side effects. Coinfection with HCV leads to a more rapid progression from HIV to full-blown AIDS. Conversely, co-infection with the HIV accelerates the deterioration from HCV infection [46]. In a number of patients, our remedy has cleared either HBV or HCV or both in HIVinfected patients. It would appear that our HIV therapeutic vaccine primes normal immunocompetent cells to selectively recognize cells infected with HIV, HBV and/or HCV as abnormal, and thereby trigger off the cytotoxic destruction of such infected cells. In those with HIV infection, this process also destroys the provirus, leading eventually to the complete eradication of the HIV from the person’s body. It seems that immunocompetent cells that have been primed by our remedy to selectively recognize and cause the destruction of HIV-1 infected cells are also able to do the same to cells infected by HIV-2, HBV and HCV. Peripheral blood CD4 counts are used to stage HIV infection and to predict the course of HIV disease. Any therapy that results in the elevation of CD4 counts in an HIV-infected person is considered clinically beneficial. The following Table shows the effects of our HIV therapeutic vaccine on CD4 counts. The retrospective statistical analysis using the F-test of the pre- and intra-treatment CD4 counts of patients on our therapeutic vaccine showed that CD4 counts rose steadily from a mean baseline of 382 + 10.7 cells per microlitre with the highest level in CD4 counts occurring four months after therapy began (517.3 + 40.5; p = 5.1 x 10-13). As the usual cut-off value for p is equal or less than 0.05 i.e., 5 x 10-2, the results were highly significant [47]. Our remedy, being a pure human blood component extract/product literally lacks toxicity. It should also be compatible with any other drugs or vaccines. As much as possible however, we avoid combining it with antiretrovirals or herbal preparations so that we know what effects are attributable to our therapy. Our remedy offers a lot of hope for the millions infected with the HIV, HBV and HCV. Its use is not associated with any stigmatizing antibody production, and is very safe. Lyophilization would likely prolong the lifespan of the vaccines. Its outpatient administration

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makes it very suitable for use everywhere especially in developing countries that harbour the vast majority of those infected with these lethal viruses, the HBV, HCV and HIV. Unlike antiretrovirals, our remedy can readily be administered by nursing and other health professionals competent to administer intramuscular injections. We believe that it is possible for the vaccines to be mass-produced for mass application. We believe that more research needs to be done for a proper and better elucidation of the mode of action of our HIV vaccines and for possible improvements on the vaccines that we are presently using. Table of summary of the differential CD4 counts according to number of patients and time on our therapeutic HIV vaccine therapy compared to baseline CD4 cell counts Number of visits Number of patients available available for analysis Median number of days from First visit ± standard error Approx. number of wks from 1st visit Mean CD4 counts± standard error Difference in absolute CD4 numbers from baseline Difference expressed as % from baseline p-value compared to baseline

1st 272

2nd 272

3rd 159

4th 98

5th 67

6th 46

7th 32

8th 21

9th 17

-

25± 12.3

62± 17.4

94± 28.9

112± 22.7

160± 33.8

194± 43.7

244± 31.0

289± 53.1

-

4

9

13

16

23

28

35

41

382.2 ±10.7 -

389.7 ±11.8 7.5

446.9 ±21.2 64.7

510.0 ±29.4 127.8

517.3 ±40.5 135

447.1 ±40.8 64.9

419.6 ±43.9 37.4

405.8 ±52.2 23.5

346.7 ±28.9 -35.5

-

1.9

14.5

25.1

26.1

14.5

8.9

5.8

-10.2

-

0.11

2.2 x 10-9

1.8 x 10-10

5.1 x 10-13

1.1 x 10-5

0.005

0.036

0.069

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VEHEMENT RESISTANCE TO ATTEMPTS TO LOCK UP OUR HIV VACCINES Non-malicious doubts and constructive criticisms, the twin pillars that advance the frontiers of medicine (and science) are normal and routine daily occurrences in the medical profession during the presentation of patients at ward rounds or clinical meetings, and at conferences/workshops. We are all used to it in the medical profession. Accordingly, we expected that the HIV vaccines we have developed would be received with aggressive doubts and ferocious criticisms especially from our colleagues, HIV vaccine ‘experts’, researchers and developers as well as others. On the other hand, we were professionally and morally bound to let HIV-infected persons know about the discovery so that those who choose may avail themselves of the development - as Physicians, the health of the patient is always our first consideration! We also had to reckon with the international politics of HIV vaccines development, the economic and socio-political interests of any country that develops them, and other related issues. We recalled how those countries with nuclear capability have continued, for decades to guard it with the entire arsenal in their possession up till now so that others would not get

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the technological know-how even though it is a scientific matter being used for military purposes. We also recalled that even for ordinary soft drinks, the Coca-Cola Company has, for decades kept the formulation for its Coke drink a highly guarded secret because of their economic interest. Most new developments in medicine are normally reported in Journals mainly for the benefit of informing other colleagues who would then use the development as they consider best in the interest of their patients. Some others however announce it at Press conferences if they think it is a serious public health issue or it is in their country’s interest to do so. However, the publication of any new discovery is not as easy and straight forward as that. It takes time and patience. When the development conflicts with the entrenched concepts of the time, one would find it extremely difficult to get any Journal to publish it. Peer review of manuscripts is standard practice in the medical fields before acceptance for publication. Which editor would agree to even send any manuscript from us at the 1998 stage for peer review? And who would peer review and recommend for publication the sort of developments we had made on HIV therapeutic vaccine? We had just 4 cured cases of HIV infection, the result of a secret personal hobby. We reminded ourselves of Jenner’s experience when he laboured in vain to get his work on smallpox vaccine published. We also recalled the difficulties that faced Albert Einstein when he tried to get his work on relativity published - the work was beyond the comprehension of those to publish them! Which medical Journals or its peer reviewers would publish or recommend for publication the discovery of safe and effective HIV vaccines developed by a single-handed researcher working in a developing country when they have already been indoctrinated that such vaccines are at least a decade away, that such vaccines can only be conceived in the laboratories of the developed countries, that such vaccines require intense international cooperation, etc? So, forget about trying to publish at the 1998 stage. Instead, concentrate on getting more data before attempting any kind of publication. We tried hard to marry these various interests and considerations. So much water has passed under the bridge since we had the first cases of cure of HIV infection in December 1998 that there would not be room here to state them all in this chapter. We will therefore limit it to just some of the developments that took place in 1999 and 2000 (Appendices 1-29). The author’s lot is nothing new in science and other human endeavours. When the Wright bothers, mere bicycle repairers, developed the first aeroplane in 1904, they were roundly condemned by virtually all the leading US gravitational scientists of their time! Their great achievement, I was told in Primary School history lessons, was reported by only 4 newspapers in the entire United States! Yet their discovery has radically and positively changed man’s existence on this terrestrial ball. If human beings were logical creatures, the development of safe and effective HIV vaccines anywhere in the world would have been welcome news everywhere. It is indeed a truism that ‘When dealing with people, let us remember we are not dealing with creatures of logic. We are dealing with creatures of emotion, creatures bristling with prejudices and motivated by pride and vanity’ [48].

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Even the publication of, and about our HIV vaccine development effort in many journals [5,36,37,44,47,49,50] has not been enough to stimulate the CNN, the VOA, the BBC, the AFP and Reuters to report the development and/or carry out their own independent investigation into the claim! Nigeria’s National Action Committee on HIV/AIDS (NACA), headed by a Professor of Medicine has not only been one of our most vocal critics in Nigeria, it had been saying publicly that if we were genuine in our HIV vaccines claims, we should get our work published in a medical Journal. However, when I confronted the same head of NACA in 2004 with the publication [36] of our work, he said, in a volte face, “Publication does not mean acceptance to the Government.” From 29 May 1999 to 29 May 2007, the Nigerian Government under President Obasanjo mounted a sustained, open malice, ill will and deliberate premeditated malevolence and opposition to the author and his HIV vaccines (Appendices 20, 21, 24-26). It is therefore clear from the Appendices that not only the Government of the author’s country but the United Nations, some pharmaceutical companies, the Governments of some developed nations and their institutions of mass communications such as the CNN, and others are prepared to go to any extent to lock up the discovery of these vaccines because of various reasons such as corruption, greed, protection of huge investments in antiretrovirals, economic race for their company that comes up with the first successful HIV vaccine shot (such a company would have “a license to print money.” “You’re talking about billions and billions of dollars,”) [Appendix 33], bristling prejudices, pride and/or vanity. They would not even investigate the claim for authenticity. The CNN did not respond in any way to the e-mail we sent to them in 2004 about our work (Appendix 27). Is it a deliberate policy of the CNN that they must never give our discovery any coverage at all even though they know, or ought to know that by doing what they have been doing, they were literally killing many HIV-infected persons? Yet, the same CNN, on 22-23 September 2007, carried this on its NEWSBAR,

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‘Merck drops trials of HIV vaccine after test fails’ The CNN always telecasts such developments like Merck’s [Appendix 33] as news but the successful development of safe and effective vaccines in Nigeria since 1999 is not newsworthy to the CNN. The sort of HIV vaccine news that interests the CNN seems to be the stale one of failure by their researchers and pharmaceutical companies even though these failures have been the recurring decimal since 1984! We have been trying in vain to get our work published since 2000. Most of the leading international medical journals have got such rigid ideas about how and where HIV vaccines would be developed that they are completely unable to recognize that other possibilities exist. In this regard, we owe much to Prof R. E. Spier for publishing our report in 2004 [5,36]. He is not just a rare scientist imbued with a very open scientific mind; he is a very courageous scientist who stands by his convictions. He stuck his head out for the truth in order to advance the frontiers of medical knowledge and understanding in the fight against HIV/AIDS. Our first manuscript reached him in June 2003. He critically and meticulously looked into our raw data for several months before he eventually advised us to write another

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47

submission, a report that took into consideration his suggestions. We submitted the report at the end of December 2003. That report was eventually accepted for publication 6 months later! It took another 3 months before the publication came out. Without him, it is likely that we would have still been struggling in vain to get our work published. His editorial that preceded our published report says it all [5].

CONCLUSION Learning from history and taking a critical look at the factors that have led to persistent failure at developing safe and effective HIV vaccines since 1984, the author has been able to successfully conceive, design, develop and apply safe and effective HIV therapeutic and preventive vaccines since 1997 and 1999 respectively. As a very welcome side effect, the HIV therapeutic vaccine causes serodeconversion for HBsAg and anti-HCV IgG antibodies in some HIV-infected patients. The author carried out his research single-handedly, using just his family’s resources. Despite the publication of, and about his breakthrough on HIV vaccines development, the author’s own country Nigeria, the UN, researchers and scientists, the Governments of many developed countries and their institutions of mass communication such as the CNN and VOA have been at their best to get the author’s HIV vaccine work permanently locked up. The author’s HIV vaccine work cannot be perfect. It is just a new development and requires the inputs of others to improve the quality of the vaccines, to help make them globally available at affordable price to those in need of them, to try to elucidate the mode of action of the vaccines, etc. The author is indebted to all his patients. He is also deeply grateful to all those who have contributed in one way or the other to letting others know about his work especially the electronic and print media in Nigeria as well as to Prof. Spier, the Vaccine editor who was the first to publish a report of his work in their international Journal. He is also very grateful to those that offered suggestions, encouragement and/or constructive criticisms and to the publishers of this book for not only spontaneously inviting him to contribute this chapter but also for accepting to publish it.

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APPENDICES Appendix 1 On 25/2/1999, I wrote a letter Ref MSH-99225-BE thus: “The Ambassador British Embassy Abuja. Dear sir, The worldwide, dreadful and killer disease, AIDS (Acquired Immune Deficiency Syndrome), caused by the Human Immunodeficiency Virus (HIV), has so far defied efforts at finding an effective and safe remedy, either curative or preventive. Consequently, HIV infection has become Mankind’s scourge and albatross.

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I have been involved, through a personal decision, in the research to try and develop a safe and effective remedy for HIV since early 1992, using my own resources on a problem in which there is very little to guide a researcher in Nigeria, but I stubbornly persisted. It is my delight to inform you that my research has resulted in the availability of a safe and effective treatment for HIV infection. Yours truly, (signed) JOA Abalaka, MB.BS (ABU 1972), FMCS (1979), Cert. Immunol (Unibadan 1974), Chief Consultant Surgeon/Chief Medical Director.” Note. Appendix 8 is the response I received.

Appendix 2

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On 25/2/1999, I wrote a letter Ref MSH-99225-FE thus: “The 1st Secretary French Embassy Abuja. Dear sir, The Human Immunodeficiency Virus (HIV), the causative agent of the dreaded and dreadful disease, AIDS, has so far defied man’s attempt at finding an effective and safe remedy. Consequently, mankind has been standing nakedly before the HIV pandemic. By a personal decision, I joined others in early 1992 to face the HIV challenge by becoming involved in a research to try and find a remedy against the HIV, carrying out the exercise with my own resources. From my research, I am delighted to inform you that a safe and effective treatment for the infection is now available with the undersigned. Yours truly, (signed) JOA Abalaka, MB.BS (ABU 1972), FMCS (1979), Cert. Immunol (Unibadan 1974), Chief Consultant Surgeon/Chief Medical Director.” Note. I have received no response.

Appendix 3 On 3rd March, 1999, I wrote a second letter Ref MSH-9933-BE in these words: “The Ambassador British Embassy Abuja. Dear sir, SAFE EFFECTIVE TREATMENT OF HIV INFECTION With reference to my letter No. MSH-99225-BE of 25/2/99, I apologise for forgetting to introduce myself to you. I would like to do so in this letter, please.

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I am one of the 1972 pioneer medical graduates of Ahmadu Bello University, Zaria, and I have been in continuous medical practice since then. In 1974, I completed a postgraduate Certificate course in Immunology from the University of Ibadan. In 1976, I passed the specialist examination in Surgery, and became a Fellow of the Nigeria Medical Council in Surgery in 1979. For more detailed information, I enclose a copy of my C.V. for your perusal, please. Kind regards. Yours faithfully, (signed) JOA Abalaka Chief Consultant Surgeon/Medical Director. Enc.” Note. The CV mentioned is reproduced in Appendix 7. I have not received a response to this letter.

Appendix 4

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On 3rd March, 1999, I wrote a second letter Ref MSH-9933-FE in these words: “The 1st Secretary French Embassy Abuja. Dear sir, SAFE EFFECTIVE TREATMENT OF HIV INFECTION With reference to my letter No. MSH-99225-FE of 25/2/99, I am sorry I forgot to introduce myself to you. Please allow me to do so in this letter. I am one of the pioneer medical graduates of Ahmadu Bello University, Zaria. While working as a Senior House Officer in the Pathology Department at that University’s Hospital in 1974, I successfully completed a postgraduate Certificate course in Immunology at the University of Ibadan. Two years later, I obtained my Specialist qualification in Surgery, and in 1979, became a Fellow of the Nigeria Medical Council in Surgery. I have been in continuous medical practice since graduation in 1972. I attach herewith a copy of my C.V. for your information. Kind regards. Yours faithfully, (signed) JOA Abalaka Chief Consultant Surgeon/Medical Director. Enc.” Note. The CV mentioned is reproduced in Appendix 7. I have not received a response to this letter.

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On 3rd March, 1999, I wrote a second letter Ref MSH-9933-USIS in these words: “The Director United States Information Service Abuja. Dear sir, SAFE EFFECTIVE TREATMENT OF HIV INFECTION Let me sincerely apologise for forgetting to introduce myself in my earlier letter No. MSH-99225-USIS. Do please permit me to do so in this letter. I am one of the 1972 pioneer medical graduates of Ahmadu Bello University, Zaria, and have been in continuous medical practice thereafter. In 1974, I completed a postgraduate Certificate course in Immunology at the University of Ibadan. In 1976, I specialised as a Surgeon, and became a Fellow of the Nigeria Medical Council in Surgery in 1979. For more detailed information, I enclose a copy of my C.V., please. With kind regards. Yours sincerely, (signed) JOA Abalaka Chief Consultant /Medical Director. Enc.” Note. The CV mentioned is reproduced in Appendix 7. I have not received a response to this letter.

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Appendix 6 As a little village boy in the 1950’s , I recall vividly the yaws affliction suffered by almost all children because yaws was then endemic in central Nigeria. Relief eventually came for the affected children when UNICEF vehicles arrived, giving free intramuscular injections to everyone. A few weeks later, they returned and repeated the injections. That procedure eradicated yaws completely up till today. I was thrilled to learn as a medical student 15 years later, in 1969, that the wonder injection that dealt with yaws was a long-acting form of the antibiotic Penicillin, PAM, Penicillin in Aluminium Monostearate. Professor Edington under whom I received training in Histopathology repeatedly told me then that a good theoretical and practical knowledge of the then young field of Immunology was an absolute requisite for anyone wishing to make any significant contribution/progress in any field of Medicine especially in Pathology. Accordingly, he sent me to the University of Ibadan where I successfully completed a postgraduate Certificate course in Immunology in October 1974. He also arranged for me to participate in a two-week WHO-sponsored Immunopathological Conference on Schistosomiasis in Geneva, Switzerland that year (Suisse visa No. 2370 issued to me by the Suisse Embassy in Lagos on 19 September 1974). I will continue to acknowledge with immense gratitude that without the knowledge and practical

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experience I gained from that WHO-sponsored Immunopathological Conference in Geneva in 1974, it would have been impossible for me to venture into HIV vaccine development in 1992. For the above reasons, I still believe I owe more to the United Nations and WHO than many other doctors. I was therefore bubbling with enthusiasm, optimism and profound gratitude to the WHO when on March 5, 1999, I wrote a letter Ref. MSH-9935-WHO in these words:‘The Co-ordinator World Health Organisation Lagos. Dear sir, BPPP CRESTVAC, AN INNOVATORY, NON-TOXIC AND EFFECTIVE TREATMENT FOR HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION I wish to inform you that I have developed the BPPP CRESTVAC, an effective and nontoxic therapy against the HIV. I am one of the first set of doctors produced by the Ahmadu Bello University, Zaria in June, 1972. While working as a Senior House Officer (Pathology) at that University’s Teaching Hospital in Zaria, I successfully completed a postgraduate Certificate course in Immunology at the University of Ibadan in 1974. I specialised in Surgery in 1976, and obtained the surgical Fellowship of the Nigeria Medical Council in 1979. In case you would like to have more information about me, I enclose a copy of my C.V. please. I decided in 1992 to join the many others worldwide who are involved in trying to find a remedy for the HIV pandemic, using my own resources. In 1997, I was ready for the first clinical trials, using the innovatory immunotherapy I had developed. A year later, their sera which had contained anti-HIV1 antibodies before treatment began, had become negative for anti-HIV antibodies. TCD4 lymphocyte counts, where low before treatment, rise to normal levels within a month of commencing treatment. Pari passu with these were clinical evidence of improvement in the patients’ symptoms attributable to HIV infection. Though an outpatient procedure, the innovatory BPPP CRESTVAC immunotherapy requires, for now, the physical presence of the person for the therapy to be administered. BPPP CRESTVAC involves the administration of a number of doses during the first 30 days followed by booster doses over the subsequent months. I believe you would be interested in this development, and that you would like to let others know about it so that those who wish may avail themselves of this golden opportunity of ridding themselves of the dreaded HIV infection. With kind regards and best wishes. Yours sincerely, (signed) JOA Abalaka, MB.BS, FMCS, Cert. IMMUNOL., Chief Consultant Surgeon/Medical Director. Enc.” Note. The CV mentioned is reproduced in Appendix 7. I have not received a response to this letter.

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This is the Curriculum vitae mentioned in Appendices 3-6 & 9. CURRICULUM VITAE OF DR. J. O. A. ABALAKA A. PERSONAL PROFILE 1. Surname Other names 2. Sex 3. Date of Birth 4. Place of Birth 5. Nationality 6. Family Status 7. Next of kin 8. Current post held

ABALAKA Jeremiah Ojonemi Alabi Male December 12, 1948 Ajiyolo Aboko-Oche, Dekina LGA, Kogi State Nigerian Married with 3 children Mrs. E.I.M. Alabi, c/o P.O.Box 223, Gwagwalada Chief Medical Director/Chief Consultant Surgeon Medicrest Specialist Hospital, Gwagwalada-Abuja.

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B. SCHOOLS/COLLEGES ATTENDED WITH DATES 1. Native Authority (N.A.) Junior Primary School, Abocho. Dekina LGA. Kogi State. 1956-1958. 2. N.A. Senior Primary School, Ayangba, Dekina LGA, Kogi State. 1959-1960 3. Ochaja Secondary School, Dekina LGA. Kogi State. 1961-1964 4. St. Paul’s College (now Kufena College), Zaria, Kaduna State. 1965-1966 5. Faculty of Medicine, Ahmadu Bello University, Zaria. 1967-1972 6. Faculty of Medicine, University of Ibadan. 1974 7. Postgraduate training in Surgery, A.B.U., Zaria. 1974-1979 C. EDUCATIONAL/PROFESSIONAL CERTIFICATES/QUALIFICATIONS 1. West African School Certificate, Division 1 with Distinctions (1, 2 or 3) in all 7 subjects offered in December, 1964. 2. Higher School Certificate with passes at Principal level in the 3 major subjects offered in December, 1966 3. Bachelor of Medicine, Bachelor of Surgery (MB.BS) degree with distinctions in Surgery, Obstetrics and Gynaecology, and Paediatrics in July, 1972. 4. (Postgraduate) Certificate in Immunology, passed with Distinction in October, 1974. 5. Fellowship of the Medical Council in Surgery (FMCS) Part I, a specialist qualification equivalent to the British FRCS, November 1976. 6. FMCS Part II (Final), a professional qualification that entitles holder to be appointed Consultant in Surgery anywhere in Nigeria, November 1979. D. PRIZES/DISTINCTIONS FOR ACADEMIC/PROFESSIONAL EXCELLENCE 1. Numerous prizes in various subjects and for being the best student in Forms I, III, IV and V in secondary school (double promotion from Form I to III), 1961-1964

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2. Class prizes for the best Science student in both the Lower Sixth and the Upper Sixth classes, and for the best student in Physics and in Zoology in the Upper Sixth Form in 1966 at St. Paul’s College, Zaria. 1965-1966. 3. St. Paul’s College runner-up prize of the American Embassy 1966 National John F. Kennedy Memorial Essay Competition for Upper Sixth Form students. 1966. 4. Distinctions in Chemistry, Physiology, Biochemistry, Microbiology, Community Medicine, Surgery, Obstetrics and Gynaecology, and Paediatrics during undergraduate training at A.B.U., Zaria. 1967-1972. 5. Vice-Chancellor’s Prize for the best all-round graduating medical student from the Faculty of Medicine, A.B.U., Zaria. June 1972. 6. Professor Nicholson’s Prize for the best graduating student in Chemical Pathology from the Faculty of Medicine, A.B.U., Zaria. June 1972. 7. Distinction, (Postgraduate) Certificate in Immunology course, University of Ibadan. October 1974 E. WORKING EXPERIENCES WITH DATES 1. Enumerator in the National Population Censuses, 1962 and 1963. 2. Bank Clerk, Barclays Bank DCO (now Union Bank Plc). December 1966 - Sep 1967 3. Pre-registration House Officer 1972/73 ) ) 4. Senior House Officer 1973/74 ) ) with the Institute of Health, Ahmadu 5. Registrar in Surgery 1974/76 ) Bello University Teaching Hospital, ) Zaria. 1972-1979. 6. Senior Registrar II in Surgery 1976/78 ) ) 7. Senior Registrar I in Surgery 1978/79 ) 8. Clinical Attachment as post-FRCS Registrar in Surgery, Royal Infirmary and Broadgreen Hospitals, Liverpool, England. 1977/78 9. Honorary Lecturer in Surgery, Faculty of Surgery, University of Liverpool, England. 1977/78 10. Medical Officer i/c, Medical Centre, Ashaka Cement Co. Ltd. near Gombe. This was a top management post. 1979-1983 11. Assistant General Manager (later re-designated Assistant Director) i/c, Medical Services Division, Ajaokuta Steel Co. Ltd, a management post during which I was responsible directly to the General Manager/Chief Executive, Magaji M. Inuwa. 1983-1989 12. Chief Consultant Surgeon with (a) Kano State Health Services Management Board. 1989 - 1990 (b) Benue State Health Services Management Board (later deployed to Kogi State upon the creation of that State in 1991). 1990-1994 (c ) Gwagwalada Specialist Hospital, Abuja FCT. 1995 - 1997. F. OTHER APPOINTMENTS/POSITIONS OF RESPONSIBILITY HELD 1. Head of Department of Surgery at the General Hospitals at Makurdi and Lokoja

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2. Head of Department of Surgery, Gwagwalada Specialist Hospital. 3. Member (representing the Nigeria Medical Association, Kogi State Branch), Board of Directors of the Kogi State Hospitals Management Board. 4. Member, Kogi State Advisory Committee on the Prerogative of Mercy. 5. Medical Superintendent i/c, Specialist hospital, Lokoja. G. PROFESSIONAL BODIES/COUNCILS AND CONFERENCES ATTENDED 1. Fully registered as Medical Practitioner with the Nigeria Medical Council since 1973 2. Temporary Registration with the General Medical council London. 1977/78 3. Professional Conferences in Geneva, Accra, London, Liverpool, Edinburgh etc. H. HOBBIES Reading, D-I-Y maintenance, hunting, photography, chess, golf.

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Appendix 8 On 2 April 1999, I got the following posted letter from the British Embassy in Abuja: “03/03/99 JOA Abalaka, M.D Medicrest specialist hospital Gwagwalada, Abuja. Dear Dr. Abalaka, 1. Thank you for your letter of 25th Feb. 1999. 2. The contents of your letter have been noted. 3. I suspect that we will not be in a position to assist you, as in general, our funds are committed in a strategic manner to address particular areas in line with DFID’s development policies. Consequently, DFID is not in a position to get involved with the verification of such claims as are contained in your letter. 4. We would however be delighted if your claims are substantiated and wish you success in your research. Best wishes. (signed) Dr. Elizabeth Tayler Health and Population Field Manager Dept. for International Development.” Note. As can be seen in my letter (Appendix 1) that they acknowledged, I did not ask for any form of financial assistance.

Appendix 9 I wrote letter Ref MSH-99681-POO dated 18th June, 1999 to Nigeria’s President Olusegun Obasanjo thus:-

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“President Olusegun Obasanjo President of the Federal Republic of Nigeria The Presidency Aso Rock Abuja FCT Your Excellency, THE DEVELOPMENT OF A SAFE, EFFECTIVE AND CURATIVE OUTPATIENT TREATMENT FOR HIV INFECTION I am one of the June 1972 pioneer medical graduates of the Ahmadu Bello University, Zaria. While working as a Senior House Officer (Pathology) at that University’s Teaching Hospital in Zaria in 1974, I successfully completed a postgraduate course in Immunology at the University of Ibadan in October 1974. in November 1976, I specialised as a Surgeon. In November 1979, I obtained the Fellowship of the Nigeria Medical Council in Surgery. I have been in continuous clinical practice since 1972. I enclose a copy of my CV for more detailed information about me, sir. Using my own human and material resources, I decided in 1992 to join others worldwide to conduct my own research to try and develop an effective treatment for infection with the dreaded human immunodeficiency virus, HIV, the causative agent of the AIDS pandemic that has remained mankind’s albatross since the virus was discovered around 1983. It is universally accepted and acknowledged that there is yet no cure for HIV infection which is particularly very common in Nigeria and other sub-Saharan countries. From my years of research, however, I have successfully developed a safe, effective and curative outpatient treatment for the notorious HIV infection (se the pamphlet attached). Out of patriotism, I wrote on 3rd February 1999 to your predecessor General Abdulsalami Abubakar (now retired) about this momentous development, and despatched the letter to him by DHL (copy attached), but I have not received any response. I believe you would not only be interested about the discovery, but may wish to take further action as Your Excellency deems fit on the matter, sir. Thank you indeed for sparing your precious time to read this letter. Yours truly (signed) Dr. JOA Abalaka, MB.BS (ABU 1972), FMCS (1979), Cert. Immunol (Unibadan 1974), Chief Consultant Surgeon/Chief Medical Director.” Note. The CV mentioned is Appendix 7. I have not received any response up till today.

Appendix 10 I wrote a letter and widely distributed it before or by June 18, 1999 to, among others, Nigeria’s Federal Ministries of Health, Science and Technology, Information, and Defence, The Medical and Dental Council of Nigeria, The Chief Physician to President Olusegun Obasanjo, Dr. Ajumo,

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The Chief Physician (Dr. Wali) to General Abdulsalami Abubakar (Rtd), Obasanjo’s predecessor The Nigeria Medical Association The Chief Medical Directors of all the University Teaching Hospitals in Nigeria The Chief Medical Directors of all the Federal Medical Centres in Nigeria The Guild of Medical Directors in Nigeria The Pharmaceutical Society of Nigeria The National Institute for Pharmaceutical Research and Development (NIPRD) The Institute of Medical Laboratory Scientists of Nigeria The Nursing and Midwifery Council of Nigeria The World Health Organisation (WHO) in Nigeria The President of Nigeria’s Senate The Speaker of Nigeria’s House of Representatives The British and French Embassies in Nigeria The United States Information Service in Nigeria The Chief Justice of Nigeria Some multinational companies in Nigeria involved in the marketing and distribution of antiretroviral drugs, GlaxoWellcome, Roche, Neimeth (formerly called Pfizer). The vast majority of them did not respond in any way to the letter that was worded thus: “Dear sir/madam, AVAILABILITY OF A SAFE AND EFFECTIVE CURATIVE OUTPATIENT THERAPY FOR HIV INFECTION Using my own human and material resources, I have, since early 1992, been involved in research to try and find a safe and effective treatment for HIV infection. My research led to the development of an innovatory treatment which I started administering on some HIV infected persons about the end of 1997, with their free and informed consent. By the end of 1998, some of them had seroreverted to anti-HIV antibody negative. Since then, another patient who had the treatment has shown up. He too has seroreverted, and has normal haematological and biochemical profiles. Presently, there are a number of HIV positive patients currently receiving the treatment; they are doing well clinically, with marked improvements in their general well-being, weight gain, rise in CD4 counts, and other monitoring profiles, just like those who had seroreverted. I expect these people to serorevert after 18-24 months of treatment. The findings from my research so far show that a safe, effective, and curative outpatient treatment for HIV infection has indeed been developed (see a copy of the pamphlet attached). You may therefore, wish, in the greater interest of humanity and HIV infected persons, to take action as you deem appropriate. With best wishes and kind regards indeed. Yours sincerely, (signed) JOA Abalaka, MB.BS (ABU 1972), FMCS (1979), Cert. Immunol (Unibadan 1974), Chief Consultant Surgeon/Chief Medical Director.”

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Appendix 11 “MEDICREST SPECIALIST HOSPITALS LTD RC No. 339502 School,

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Our Ref: MSH.99802.HM.MOH Your Ref: The Honourable Minister of Health Federal Ministry of Health New Federal Secretariat Garki, Abuja. Honourable Minister sir,

Opp. Demonstration Day Primary

P. O. Box 382, Near NEPA Substation, Gwagwalada, Abuja F.C.T. Date: 20th August, 1999

REMINDER - AVAILABILITY OF CURATIVE IMMUNOTHERAPY FOR HIV INFECTION Let me again congratulate you whole-heartedly for your appointment as the Honourable Minister of Health at this crucial time in our national history and progress. I had earlier posted a Congratulation Card to you on your being sworn in. I still sincerely wish you God’s guidance, guardance and wisdom in everything you do and handle. I am a Chief Consultant Surgeon with some postgraduate training in Immunology. I am in private medical practice here in Abuja FCT. I have developed a safe and effective outpatient curative immunotherapy for the dreaded HIV infection, after years of personal research carried out entirely with my family’s resources. As I write, 5 anti-HIV antibody positive patients have been completely cured with my novel therapy, and are now HIV antibody negative. More importantly, HIV infected patients with symptoms and who receive my immunotherapy rapidly improve in their status. The effects of the therapy are just dramatic, sir. After the present civilian administration was inaugurated, I wrote to the President (copy attached) about the discovery. Since the Ministers had not been appointed at that time, I wrote to the Permanent Secretary, Ministry of Health on 18th June, 1999 on the matter, hoping that on the appointment of Ministers, the Permanent Secretary would naturally bring the matter to the notice of whoever was sworn in as Minister of Health. Permit me then to remind you, sir, of the development about HIV therapy above narrated. I believe it would interest the Hon. Minister to know that I have completed research on the preventive vaccine for HIV infection, too. Given the facilities and necessary support, it is a simple matter for both the curative immunotherapy and preventive vaccine against HIV to be mass produced and used anywhere, including export. I have no doubt in my mind that my country stands to gain immensely from this discovery, economically, scientifically, internationally, and what have you.

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Thank you sir, for sparing your precious time to read this letter. I look forward to hearing from you as you deem fit in the circumstances. With very warm regards and best wishes indeed. Yours sincerely, (signed) JOA Abalaka, MB.BS (ABU 1972), FMCS (1979), Cert. Immunol (Unibadan 1974) Chief Consultant Surgeon/Managing Director.” Note. I did not get any reply to this letter.

Appendix 12 “RC No. 339502

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Our Ref: MSH.99802.HM.MOH Your Ref: The National AIDS Co-ordinator National AIDS 7 STD Control Programme Federal Ministry of Health New Federal Secretariat PMB 409, Garki Abuja FCT Dear sir,

Opp. Demonstration Day Primary School, P. O. Box 382, Near NEPA Substation, Gwagwalada, Abuja F.C.T. Date: 20th August, 1999

YOUR VISIT TODAY 6/8/99 Despite your busy schedule, you led a team of 3 others today on an official visit to our small Centre from around 1620 to 1830 hours. We would like to recall with appreciation the earlier visits by Dr. O. O. Soretire from your Department. His first visit, which was the first contact we received from the Ministry of Health, was on Wednesday 14/7/99 from circa 1630 to 1820 hours. He kept his promise and visited us again a week later on 21/7/99 from c. 1615 to 1820 hours. He was in your team today. All these visits were not unconnected with our claim of developing a safe and effective outpatient curative immunotherapy for the dreaded HIV after several years of research conducted entirely on our meagre resources. We sincerely thank you for the visits, sir. Kindly help us convey our gratitude to the other members of your team that came today, please. We would also like to express our gratitude to you and members of your team for the frank discussions we had, and for the advice, suggestions, constructive criticisms, and encouraging commendations about our HIV research. On our part, we have already set in motion steps to implement your suggestions and advice. Thank you very much. With regard to the NTA Newsline telecast on Sunday 1/8/99, the interview NTA had with me and which was telecast that day was actually recorded between 1230 and 1340 hours on Wednesday 14/7/99. Unfortunately, the telecast did not reveal the date and time of the

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interview. When it was telecast on 1/8/99, many thought it was current as at 1/8/99 whereas all I said in that interview was only correct as at the time and date of the interview which was on 14/7/99 around 1300 hours. I honestly did not, and could not have known that 3 hours after that NTA interview, Dr. Soretire from your Department would be at our Centre at your instance. It would have been wrong of me to have said during the NTA interview that the Ministry of Health had responded in any way to my claims about HIV treatment, for I had had no such response by that time. By the time of the telecast of the interview NTA had with me, it looked as if my utterances in that interview took place around 1/8/99 when it was telecast, whereas it was a video recording of an interview that took place over two weeks before the telecast, hence the distortion whereby it looked as if I had deliberately refused to tell NTA during the interview that the Ministry had sent an officer to me twice before 1/8/99 when the telecast took place on Newsline. I am sorry for the distortion and wrong perception even though it was not my making. Thank you for your understanding of the confusion, sir. In conclusion, we thank you sincerely for your visit this afternoon. We were, and still are, greatly encouraged by the visit and by your suggestions, advice and observations all of which are already receiving our immediate attention. I could not have been involved in a scheme to cover up the visits from your Department when I treasure the visits highly. We look forward to having more interactions with your Department and the Ministry not only for the mutual benefit of both parties, but more importantly, for the benefit of the public and HIV infected persons in our society and the entire world. With best wishes and kind regards, sir. Yours sincerely, FOR MEDICREST SPECIALIST HOSPITAL LTD (Signed) JOA Abalaka, fmcs Chief Consultant Surgeon/Medical Director.”

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Appendix 13 “Date: 11th October, 1999 The National AIDS Co-ordinator Department of AIDS Control & STD Federal Ministry of Health New Federal Secretariat Shehu Shagari Way Abuja. Dear Sir, SEROREVERSION IN HIV INFECTION FOLLOWING OUR CURATIVE THERAPY Further to your visit to us about our claim of having developed effective curative and preventive vaccines against the dreaded HIV and the meeting the Hon. Minister of Health graciously held with us on 9/9/99 on the same claim, we forward herewith 3 sera samples labelled ‘A - 12/9/99’, ‘B - 3/10/99’ and ‘C - 10/10/99’ for your scientific analysis please. All the samples are from the same patient who, not surprisingly, does not wish to be publicised.

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Your analysis of these samples will likely settle, once and for all, the doubts raised by the Ministry about our claim. You may accordingly wish to analyse the samples for antibodies to HIV using screening and confirmatory tests including titre, p24Ag, LFTs, urea, VDRL, HBsAg and such other tests as you may wish e.g., to ascertain that the sera are indeed from the same patient. We have waited in vain so far for the fulfilment of the Ministry’s promise to send us patients with HIV infection for our management. Do please let us have the results of all the tests you carry out in due course on these samples, as well as your scientific conclusions, comments and or observations. A copy of this letter is being sent to the Hon. Minister of Health for his information, please. With best wishes and warm regards. Yours sincerely, (signed) JOA Abalaka, fmcs Chief Consultant Surgeon/Managing Director” Note. There was no response to this letter either.

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Appendix 14 On the back of the complimentary card of “Dr. Nasir Sani-Gwarzo, National Coordinator, NATIONAL AIDS & STD CONTROL PROGRAMME (DEPARTMENT OF PHC & DC), Federal Ministry of Health, New Federal Secretariat, P.M.B. 409 Garki, Abuja. E-mail [email protected] tele: 09 - 5238950, 5238951” was the following handwritten message: “Dr. Abalaka, Thanks for sending the 3 samples. Urgent tests will be done on them and I will get back to you. We are also arranging a meeting for you with a team of Experts. You will hear more soon. Bye for now. (Signed) 11/10/99 DR. Sani” Note. I have not received anything about the results of the tests they said would be done up till now, despite many reminders from me. I understood that eventually, the Minister of Health was so furious with his National AIDS Coordinator for trying to investigate my claims that he ordered his removal from that post.

Appendix 15 “FEDERAL MINISTRY OF HEALTH DEPT. OF PRIMARY HEALTH CARE & DISEASE CONTROL NATIONAL AIDS / STD CONTROL PROGRAMME (NASCP) Room 4A, 018-020, Federal Secretariat, CAMPAIGN Ground Floor, Annex 1, Abuja.

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WORLD AIDS

Safe and Effective HIV Vaccines Since 1999 P. M. B. No. 409, Garki, Abuja Tel: 09 5238950, 5238951 Dr. J. O. Abalaka Medicrest Specialist Hospital Gwagwalada

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Ref: C.3329/S Date: 18th October, 1999

RE: INVITATION TO MEETING ON HIV CURATIVE THERAPY The National AIDS and STD Control Programme has constituted an expert committee to investigate your HIV curative therapy claims. Consequently, a one-day meeting has been scheduled to enable you to provide further information on your therapy. The meeting will take place on 22nd October 1999 in the Conference room of the Honourable Minister of State for Health at the Federal Secretariat, Abuja. You are expected to join the meeting at 9.00 a.m. You are requested to please attend with all documents and information that will facilitate the deliberations of the committee. Attached is a question chart to facilitate your preparation for the meeting. Please accept assurances of our highest considerations. (signed) Dr. N. Sani-Gwarzo National Coordinator (NASCP) For Honourable Minister of Health” Note. Mr. Manason Rubainu, Chief Medical Laboratory Scientist and Director, Peak Medical Laboratories delivered this letter and I read it at 2245 hours on 19/10/1999. No document was attached to the letter. I attended the meeting and held discussions with the committee. At the end the committee told me to expect an immediate press statement by the Hon Minister after which they would get in touch with me again. I have not heard from them again. The Minister did not issue any press statement either.

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Appendix 16 ‘11th November, 1999 The National AIDS Co-ordinator Department of AIDS & STD Control Programme Federal Ministry of Health New Federal Secretariat Shehu Shagari Way Abuja Dear Sir,

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RE - SEROREVERSION IN HIV INFECTION FOLLOWING OUR CURATIVE THERAPY We’re still awaiting your response to our letter dated 11th October, 1999 on the above subject please, especially the results of your analysis on the 3 samples of serum we forwarded. Despite the promise by the Ministry, we are yet to see any HIV-infected patient sent to us from, and monitored by, the Ministry for our outpatient curative therapy on payment before service basis. In our opinion, the following case further confirms the truth of our claim of possessing a curative therapy for HIV infection. By letter dated 24/9/99 (copy attached but with the patient’s name covered up for obvious reasons), the Medical Director of Express Hospitals Ltd, Kubwa, Abuja FCT, referred a young man to us for our curative treatment for HIV infection. The referral letter is couched in these words:“….. I have tested this young man in our lab and had positive Elissa (sic) result. We sent the specimen to Garki General hospital and Gwagwalada Specialist Hospital and both were reactive. … He has however not started showing any signs of Aids but seropositivity. Thanks for taking him over. We shall be delighted upon a feedback.” We confirmed his HIV-1 seropositivity (A2 category), and started him on our curative vaccination therapy on 5/10/99. When he came back a week later on 12/10/99 for his second dose of our curative treatment, another sample of his blood was taken before he received the second dose. Later tests carried out on his blood samples taken on 12/10/99 and on 21/10/99 revealed the absence of antibodies against the HIV, using screening and confirmatory tests. We gave the doctor who referred him to us a feedback as he had requested, and he too confirmed the seroreversion through tests in his lab and elsewhere. I have since discharged the cured young man for his doctor to follow him up, but with a request to the doctor to let us see the patient every 3 months. We expect him to remain seronegative, just like the others before him who had been healed by our treatment. The patient’s pre-treatment serum sample of 5/10/99 as well as his post-treatment samples of 12/10/99 and 21/10/99 are available with us, frozen, in case you are interested in carrying out your own analysis on them. It may also interest you to know that his pre-treatment serum sample of 5/10/99 was HIV viropositive with a p24Ag concentration of 3 pg/ml, whereas the subsequent post-treatment sample of 12/10/99 was HIV vironegative with no p24Ag detected. In our opinion, the above patient is most likely to be of immense interest to you because another doctor was not only looking after the patient, but he referred him to us, and he is currently still looking after the patient. You may therefore wish to get in touch with Dr. M.O.D. Abonyi of Express Hospitals Ltd, Kubwa here in the FCT to verify what we have written herein about the patient, and even more importantly, for you to see the cured patient through the doctor. We believe you would likely agree that Dr. Abonyi’s patient under discussion is an excellent case that scientifically confirms our claim of possessing a safe and effective curative therapy against HIV infection, using the HIV itself, just as the Ministry and others worldwide do with polio, measles, yellow fever, etc. our autogenous vaccine which contains no chemical additives and which does not contain virus cultured elsewhere, is certainly safer that viral vaccines like polio and measles vaccines produced from culture lines either in media or cells of other animals.

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Copies of this letter are being sent to the Honourable Minister of Health and to Dr. Abonyi for their information, please. With kind regards and best wishes. Yours sincerely, (signed) J. O. A. Abalaka Chief Consultant Surgeon/Managing Director’ Note: There was no response to this letter either.

Appendix 17

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“REF FMST/TAA/104/T/21 DATE 16th Nov, 1999 Dr. Abalaka Gwagwalada Specialist Hospital Abuja NOTIFICATION OF ASSESSMENT VISIT 1. I am to convey the Ministry’s interest in your claimed feat of AIDS Management as was presented in your discussion on the Nigerian Television Authority some weeks back. The Ministry has therefore decided to visit you and to discuss ways and means of giving your efforts the necessary encouragement and promotion. 2. You are to expect the Ministry’s team on the 30th of this month by 10.00 am to start the process. 3. We hope this date is convenient to you. If not, please convey alternative date to the undersigned. (signed) J.A. Ohaba For: Honourable Minister” Note. I received this letter from the Department of Technology Acquisition and Assessment, Federal Ministry of Science and Technology, Abuja. Mr. Jacob Ata Ohaba, Deputy Director (TAA) in that Ministry brought the letter personally at 1455 hours on 19 November, 1999, and had discussions with me before he departed. The visit never took place because the officials from the Ministry never showed up, and they did not get in touch with me to explain their failure to honour their own letter.

Appendix 18 THE GUARDIAN newspaper, Wednesday, March 1, 2000, page 7 under the caption “UN intensifies search for HIV vaccines” published as follows: ‘THE search for a preventive vaccine for the Human Immunodeficiency (HIV) which causes the Acquired Immune Deficiency Syndrome (AIDS) has intensified with a new

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initiative for development of preventive vaccines by two United Nations (UN) agencies - the World Health Organisation (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS). Support may soon come from the British government to Nigerian doctors claiming to have invented vaccines for the cure of HIV as the Health Coordinator of Department for International Development (DFID) in the British High Commission, Dr. Liz Taylor has said some monetary assistance may be given for further research into the claims. In Nigeria where an estimated 5.4 per cent of the adult population between ages 15 to 49 years (about 2.6 million people) are believed to be infected with HIV, claims of a cure have been a major issue. By the year 2003, 4.9 million adults aged 15 to 49 are expected to be living with HIV in Nigeria. Taylor told The Guardian in Abuja that: “Considering the enormity of the damages caused by the HIV/AIDS scourge in the economic development of Third World countries, there is the need for concerted global efforts to fight against it.” She stressed: “The British government’s interest only is on the discovery of the vaccine for the cure of HIV not minding where it originates. My government is prepared to support any HIV/AIDS cure by any Nigerian doctor provided those claims are substantiated with enough evidence.” The Guardian learnt that recently, the British government disbursed to international bodies $14 million grants for the purpose of seeking a breakthrough in the search for the cure of HIV/AIDS. Taylor appealed to any individual who claimed a cure for the disease to come up with concrete evidence while assuring the British government would offer both recognition and support. The search for a vaccine or cure for HIV/AIDS is important because less than 20 years after it was identified, it has become the most important infectious disease, the first cause of death in Africa and the fourth worldwide. More than 15,000 new HIV infections occur every day, most of them in developing countries, and over 33 million now live with HIV or AIDS. The WHO-UNAIDS HIV Vaccine Initiative is expected to heighten international cooperation into AIDS vaccines in the face of mounting urgency as the epidemic spreads. The initiative is guided by a new joint WHO-UNAIDS HIV Vaccine Advisory Committee which meets for the first time last week. According to the coordinator of the new initiative, Dr. Jose Esparza, “the new initiative provides an independent forum where everyone working on HIV vaccines, from North or South, from industry or from research agencies and from affected communities, can identify common ground for collaboration and coordination. This should help capitalize on the extensive experience of all organisations.” The HIV Vaccine Initiative will focus on strengthening the capacity in developing countries to ensure that vaccine trials are conducted with the highest ethical and scientific standards. A major challenge facing HIV vaccine development is finding one that will be effective worldwide, including developing countries, where 95 per cent of infections occur. “Vaccines are among the most cost-efficient interventions to prevent infectious diseases,” Prof. Barry Bloom, Dean of the Harvard School of Public Health and head of the new joint WHO-UNAIDS Vaccine Advisory Committee said , adding: “We are fortunate that

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new initiatives are being proposed to expand availability of existing vaccines in developing countries and to conduct research to develop new ones.” According to Esparza, the multitude of HIV strains and the number of potential vaccines being tested make it imperative to coordinate research efforts. “Vaccine development efforts require concentrated international coordination and collaboration, with the full involvement of industrialized and developing countries, the public and private sectors, governmental and non-governmental organizations and the pharmaceutical industry,” he said, adding: “They also require the creation of financial incentives to stimulate more research and development.”’ Note. Appendix 19 is my response to this article.

Appendix 19

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By letter Ref MSH-000301 dated March 1, 2000, I responded to the GUARDIAN article thus:‘The British High Commissioner British High Commission Dangote House Aguiyi Ironsi Street Maitama District Abuja, Nigeria. Attention: Dr. Elizabeth Tayler, Health and Population Manager, Dept for Int. Devel. Your Excellency, Re: “UN INTENSIFIES SEARCH FOR HIV VACCINES” I have just read a report credited to you with above caption in today’s GUARDIAN newspaper at page 7 therein. I must say that I am very delighted with the development especially as Dr. Liz Taylor (sic) was quoted to have said:“The British Government’s interest only is on the discovery of the vaccine for the cure of HIV not minding where it originates. My Government is prepared to support any HIV/AIDS cure by any Nigerian doctor provided those claims are substantiated with enough evidence.” According to the GUARDIAN publication, “Taylor(sic) appealed to any individual who claimed a cure for the disease to come up with concrete evidence while assuring the British government would offer both recognition and support.” Permit me, your Excellency, to remind you that on 25/2/99, I wrote a letter to you on the availability with me of a safe and effective treatment for HIV infection. I followed it up with another letter to you dated 3/3/99 in which I enclosed a copy of my CV to fully introduce myself to you. On 2/4/99, I received your posted letter dated 3/3/99 signed by Dr. Elizabeth Tayler wherein she informed me that the contents of my letter dated 25/2/99 had been noted, that she suspected you will not be in a position to assist me, and that consequently, ‘DFID is not in a position to get involved with the verification of such claims as are contained in your letter’.

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From the GUARDIAN publication hereinbefore mentioned, it seems to me that there is now a change in policy by your Embassy. Even though I have not yet received any letter from you, I presume you will accept this letter as my response to the challenge thrown by Dr. Tayler through the GUARDIAN newspaper. Accordingly, I hereby re-affirm categorically that I have indeed developed safe and very effective preventive and curative vaccines against the HIV. These vaccines have been developed from the wild HIV. I have a mountain of authentic and verifiable scientific data in support of my claim. I humbly wish to invite you to visit my small Hospital at Gwagwalada on any day and time convenient to you to see things for yourself. In the alternative, I am very willing to come over to your Embassy on this issue if you give me an appointment, your Excellency. I attach copies of the GUARDIAN publication and my previous correspondence with you for ease of reference. I look forward to hearing from you, your Excellency. Yours truly, (signed) JOA Abalaka, MB.BS, FMCS, Cert. Immunol.,’ Note. Despite a signed personal delivery of this letter on 2 March 2000 at the British High Commission in Abuja, less than 80 km from my small Hospital, I have not received any response whatsoever from the High Commission up till today! I still wonder why the High Commission that threw the challenge through the newspaper has gone into years of silence on the globally important matter of effective and safe HIV curative and preventive vaccines even though HIV/AIDS has continued to torment mankind for decades and no one else has discovered such vaccines. The silence is indeed beyond my comprehension up till today!

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Appendix 20 Almost a year after I had written to inform the Medical and Dental Council of Nigeria about my development of effective and safe HIV vaccines and received no response from them, a courier mail from the Council was delivered at my Hospital for me at 1430 hours on 26 May, 2000. I read it at 2055 hours that day. The letter, on the Council’s letter-headed paper that showed “REGISTRAR DR. C. OKWUDILI EZEANI MB.BS, FWACP, MBA, MNIM” and their address “Plot PC. 13, 25 Ahmed Onibudo Street, Victoria Island, P.M.B. 12611, Lagos, Nigeria” was couched in these words: ‘Our Ref MDCN/IP/312/14 22ND May 2000. Dr. J. Ojonemi Abalaka, Medicrest Specialist Hospital, Gwagwalada, Abuja. Dear Sir,

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INVITATION TO APPEAR BEFORE THE MEDICAL AND DENTAL PRACTITIONERS INVESTIGATING PANEL FOR INVESTIGATION The attention of the Medical and Dental Practitioners Investigating Panel has been drawn to series of publications in the news media - electronic and print - concerning your therapeutic breakthrough in the treatment of HIV. Among such publications are the following, the photocopies of which are attached herewith: i) Daily Times of 29th March, 2000 titled “NMC enjoined to censor HIV/AIDS treatment claims. ii) Publication in the Nigerian Tribune titled “HIV doctor to visit Benue”. iii) Publication in the Daily Times of 23rd February, 2000 titled “Doctors disagree with Abalaka” iv) Publication in the Guardian of 9th April, 2000 titled “AIDS Curer in Diaspora”. v) Publication in the Daily Times of 12th April, 2000 titled “AIDS cure claims spark controversy in Nigeria”. vi) Publication in the Daily Champion of 13th April, 2000 titled “AIDS Virus Abalaka cures 30 soldiers - Air Force Chief”. vii) Publication in the Sunday Champion of 23rd April, 2000 titled “A maligned prophet”. viii) Publication in the Weekend News of 6th April, 2000 titled “At last AIDS Cure Found”. There are also electronically recorded exposure of your breakthrough which may be available at the Investigation. In pursuance of Section 15(2) of the Medical and Dental Practitioners Act Cap 221 Laws of the Federation of Nigeria 1990, you are hereby required and invited to appear before the Medical and Dental Practitioners Investigating Panel which has been scheduled, for that purpose, to sit at 9.00 a.m. on Monday 26th June, 2000 at the Ibro Hotel, Okpara Avenue, Abuja. You are advised to appear before the Panel with all relevant materials that may assist you and the Panel in the process of investigation. Your attention for this purpose is also drawn to the Provisions of Rules 32 and 33 of the Rules of Professional Conduct for Medical and Dental Practitioners in Nigeria, a copy of which is herewith enclosed for your guidance. In these circumstances, it is advisable to be accompanied to the investigation by a Counsel of your choice. Yours faithfully, (signed) for Dr. T.A. Alakpa Secretary Medical & Dental Practitioners Investigating Panel. Enc.’ Note. I was fully registered as a medical practitioner with the council in July 1973. This is the only invitation I have got for disciplinary action since that time. I was not the writer of any of the publications cited. All the publications carried the names of the writers. I had not even been interviewed by the writers.

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Fortunately for me, someone had advised me to give up my HIV vaccine claim because I was fighting the interest of the Nigerian Government and that of the UN and other world powers, adding that my country’s Government had written to the UN that I was not a qualified medical doctor but a noisy quack enjoying the dividends of democracy and free speech under President Obasanjo! My source warned me to get ready for the worst from my country’s Government. I saw this letter as a smokescreen to get my name struck off the medical register after a stage-managed trial before a kangaroo disciplinary committee. Otherwise, how could anything “concerning your therapeutic breakthrough in the treatment of HIV” be professional misconduct for a doctor?

Appendix 21

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On June 10, 2000 at 1655 hours I received a letter bearing the Nigerian National Coat of Arms on its top left hand corner and stamped “RESTRICTED” in two places (at the top and at the bottom) couched in these words:‘STATE HOUSE ABUJA, NIGERIA. Reference: SH/COS/01/1/190 June 6, 2000 Dr. S.(sic) O.A. Abalaka Chief Consultant Surgeon Medicrest Specialist Hospital P.O.Box 382 Gwagwalada Abuja. Dear Dr. Abalaka, RE: SOS APPEAL ON THE LATEST DEVELOPMENT ABOUT MY HIV VACCINES I write to acknowledge the receipt of your letter of May 26, 2000 addressed to the President, Commander-In-Chief, on the above subject and to inform you that it is receiving due attention. As a matter of fact, it has been referred to the relevant authorities to look into as deemed appropriate, 2. I am to advise nevertheless that you may also find it useful to seek redress about your complaint either from the courts or the National Human Rights Commission. Yours sincerely, (signed) Ambassador A.O. Esan Deputy Chief of Staff for: Chief of Staff to the President, C-In-C’ Note. Nigeria’s Medical and Dental Council is under the control of the Minister of Health. After I got this letter as the President’s response to my appeal to him over the letter I

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received from the Council (Appendix 20), I was convinced that there was substance in the warning I had been given. I then went to court. Fortunately for me, the court restrained the Council from proceeding with their stage-managed disciplinary investigation.

Appendix 22

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United Nations Organization & World Health Organization At 13:26:32 and 13:52:44 on Sunday, June 11, 2000, I sent emails to [email protected] and [email protected] respectively with the following identical wording:“Subject: HIV Vaccines Let me congratulate you for the global impact of your organization. You have done a lot for mankind in the area of objective and prompt news dissemination. HIV concerns all humanity. The raging pandemic has defied effective and safe vaccines so far. However, I developed safe and effective HIV preventive and curative vaccines since 1998/99 following a solo scientific research funded completely by my family resources. I wrote in February/March 1999 to the embassies of Great Britain, France and United States in Nigeria as well as the world health organization coordinator in Nigeria but they have all kept mute over the development. Is it because the discovery of these HIV vaccines has not come from the developed countries? One finds it difficult to understand the basis for the silence from these countries and the WHO. Would you be kind and objective as usual and publicize this short letter please? Thank you. Yours Sincerely, Dr. Jeremiah Ojonemi Alabi Abalaka, MB.BS(ABU, Zaria 1972), FMCS(Nig 1979) Cert Immunology (Unibadan, 1974) Chief Consultant Surgeon (Medicrest Specialist Hospital) Note. The UN has not responded up till now even though its Secretary-General then, Kofi Annan, is a Ghanaian from sub-Saharan Africa that is worst hit by HIV/AIDS. However, the WHO responded (Appendix 23).

Appendix 23 “Date: Sun, 18 Jun 2000 06:08:20 PDT From: [email protected] To: [email protected] Subject: HIV Vaccines Dear Dr. Abalaka, Your message to UNAIDS regarding HIV vaccines was passed on to me. We have read about your candidate product in the Nigerian lay press, but we are not aware of any scientific publication which could assist us in assessing the validity of your

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claim. We do not have any information about the candidate vaccines, nor we have information about the results from any clinical trials. If you so wish, WHO-UNAIDS and its Vaccine Advisory Committee could review the data. Sincerely yours, Jose Esparza MD, PhD Coordinator WHO-UNAIDS HIV Vaccine Initiative (HVI) Health Technology and Pharmaceuticals (HTP) World Health Organization (WHO) 20 avenue Appia 1211 Geneva 27 Switzerland Tel: 41 22 791 4392 Fax: 41 22 791 4865 e-mail: [email protected]; [email protected]” Note. When Dr. Esparza stated that they read about my candidate product in the Nigerian lay press, I wonder if the letter I wrote to the WHO Coordinator in Nigeria on 5 March 1999 (Appendix 6) was not passed on to them. He also mentioned that he was unaware of any scientific publication of my work. There was no such publication at that time. However, despite many subsequent scientific publications [5, 36, 37, 44, 47, 49, 50] of, and about my work, there has been no response from UNAIDS, the WHO and the UN. In any case, I responded to his email (Appendix 24)

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Appendix 24 On June 20, 2000, I replied Dr. Esparza’s email thus:“Dear Dr. Esparza, Thank you very much for your kind and pleasant email letter that I have just received. I am particularly grateful for your prompt response to the matter that had just been passed to you. I am happy that you are a professional medical colleague, and as such we can discuss at the same wavelength as medical practitioners bound by the Physician’s Oath that we both took. As physicians, the health of our patients shall be our first concern. The health of HIVinfected persons shall be our first concern, not scientific publication, research protocol, ethical considerations, laboratory facilities, modern research facilities or any other issue. Our first consideration, as far as HIV is concerned, shall be the health of HIV-infected persons and the health of millions worldwide that are at risk of acquiring the rampaging infection unless protected by a safe and effective HIV vaccine. In this regard, I wish to congratulate the WHO and UNAIDS for all their concern and efforts aimed at getting effective and safe HIV preventive and curative vaccines. I have through a solo scientific research that started in 1992 developed safe and effective HIV curative and preventive vaccines. If you wish to have more information, you may wish

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to turn to my website http//www.medicrest.com for more information. To achieve these targets, I have used myself as the sacrificial experimental guinea pig through my research, something other researchers worldwide have not done, and would not dream of doing. I believe you would agree that the crucial issues are these:(1) Are the vaccines safe? (2) Are the vaccines effective? The vaccines are indeed very safe and effective both in preventing HIV infection in those seronegative persons that are given the preventive vaccine, and in providing sterilization of the tissues and blood of HIV-infected patients that receive the curative vaccine and who consequently revert to anti-HIV antibody negative status. The preventive vaccine is a single dose vaccine administered by i.m. injection. The curative vaccine is given by the same route as an outpatient procedure, weekly during the first month and monthly thereafter until the patient reverts to seronegative status. Since you mentioned scientific publication, I have since sent my scientific paper captioned ‘Solo voyage with the HIV-1 in Nigeria since 1992’ to the Lancet for publication. The Lancet has allocated the article the reference number OOART/4325. the article is still undergoing processing by the Journal, a process that takes several weeks, as you know. You may wish to confirm from the Lancet if you so desire. I have given many doctors in Nigeria my HIV curative vaccine for their use on their patients to independently monitor its efficacy, safety or otherwise. It would likely interest you to know they have all found them highly effective and safe. My HIV curative vaccines ameliorate patients’ symptoms attributable to HIV-induced immunosuppression with lightening speed, sir. Over 1300 HIV-infected patients have registered with me since January 1999. the safety and efficacy of my vaccines are unbelievable, but they are true facts. UNAIDS Executive Director, Dr. Peter Piot was in Nigeria around March/April this year. He made no effort to ask me to see him, yet he took the unprecedented and unscientific approach of publicly condemning my vaccines, much against the ethics of our noble profession. I was disappointed that he could condescend to that level. However, his actions and utterances while here in Nigeria confirm that he is opposed to my vaccines just because I am not from the developed countries. It is unfortunate. It is my sincere hope that you are not as biased and prejudiced as Dr. Peter Piot. What the world has been looking for are effective and safe HIV curative and preventive vaccines. They have since been developed through a solo scientific research effort by Nigeria, using just family funds for the exercise. Despite 6 intravenous administration of HIV-infected blood administered to myself since I took the preventive vaccine last year, I have remained HIV sero and vironegative. What further scientific evidence can one get of the efficacy and safety of the preventive vaccine, Sir? I look forward to hearing from you. Meanwhile, I would assure you of my full cooperation at all times provided I have every reason to believe there is no racial prejudice against my scientific solo HIV research using family resources with no other funds from anywhere since 1992. With warm regards and best wishes indeed. Yours sincerely, Dr. Jeremiah Abalaka, MB.BS(1972), FMCS(1979), Cert. Immunology(1974)

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Chief Consultant Surgeon June 20, 2000 Tele: 234 9 8822 061 or 8822 161 or 8822 100 Fax: 234 9 8822 099 e-mail [email protected]; [email protected]” Note. I have not received any response whatsoever from Dr. Esparza since then.

Appendix 25

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“FMI/011/PRJ/HMI Doctor J. Abalaka Gwagwalada, Abuja.

24 July 2000

REQUEST FOR A PRIVATE AUDIENCE The Honourable Minister of Information, Professor Jerry Gana, has received a message from the United States, seeking his assistance in co-ordinating the visit to Nigeria of Mr. Jim McDermott, Chairman of the US Congressional Task Force on HIV/AIDS, from 29th July to 2nd August, 2000. 2. In addition to his programme in Nigeria, the visitor has requested that an audience with some Non Governmental Organisations be facilitated. The aim of his visit is to seek comments and suggestions from those involved in HIV/AIDS prevention and management programmes in Nigeria, and those employed to fight the spread of HIV/AIDS. This is with the hope of improving legislation that will radically change how the United States supports HIV/AIDS prevention programmes and facilitate the Congressional Task Force’s purpose of educating the United States Congress about the social and economic impacts of the global HIV/AIDS epidemic. 3. I am therefore directed to make a private appointment for the visitor and his entourage against Tuesday, 1st August, 2000, at your hospital in Gwagwalada. According to the itinerary prepared for Mr. McDermott, he will arrive your hospital at 2.30 p.m. Please accept the assurance of Professor Jerry Gana’s high regards. (signed) J.K. Lawal For: Honourable Minister” The following programme for the visit was attached to the letter:Program of the visit of a United States delegation led by Congressman Jim McDermott from the 29th July to August 2nd 2000 DATE SAT. 29TH JULY SUNDAY

ACTIVITY DELEGATION ARRIVES ON BRITISH AIRWAYS NO BA2075 CHURCH SERVICE

VENUE NNAMDI AZIKIWE INT. AIRPORT, ABUJA

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Continued. DATE 30TH JULY MONDAY 31ST JULY

TUES. 1ST AUG

ACTIVITY & AUDIENCE WITH MR. PRESIDENT DELEGATION DEPARTS ABUJA DELEGATION ARRIVES EKO HOLIDAY INN DELEGATION ARRIVES STATE HOUSE, ALAUSA DELEGATION RETURNS TO EKO HOLIDAY INN DELEGATION ARRIVES ABUJA AUDIENCE WITH HON. MINISTER OF DEFENCE AUDIENCE WITH HON. MINISTER OF HEALTH AUDIENCE WITH NACA/NACP & NGOs VISIT TO HOSPITALS AND AUDIENCE WITH MORE NGOs AUDIENCE WITH ABUJA CHAMBER OF COMMERCE BRIEF AUDIENCE WITH HON. MINISTER OF INFORMATION RECEPTION

WED.2ND AUGUST

DELEGATION DEPARTS NIGERIA

VENUE STATE HOUSE NNAMDI AZIKIWE INT. VICTORIA ISLAND LAGOS

TIME 1 P.M. 8 A.M. 11.55 A.M

IKEJA

2.50 P.M.

VICTORIA ISLAND LAGOS NNAMDI AZIKIWE INT.

5 P.M. 10 A.M.

DEFENCE HQTS. ABUJA CONFERENCE ROOM FED. MIN.OF HEALTH CONFERENCE ROOM FED. MIN.OF HEALTH GWAGWALADA INTERNATIONAL WOMEN CENTRE RADIO HOUSE NICON HILTON HOTEL NNAMDI AZIKIWE INT. AIRPORT

11.30 A.M. 12 NOON 2.30 P.M 5 P.M. 6.30 P.M. 7.30 P.M.

Note. Congressman Mr. Jim McDermott, Chairman of the US Congressional Task Force on HIV/AIDS and his team verily visited me as scheduled. We discussed my work for over an hour. They left promising they would take it up. I have not heard anything from the Chairman since they left.

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Appendix 26 NIGERIA’S THEN VICE-PRESIDENT ALHAJI ATIKU ABUBAKAR The Post Express newspaper, Tuesday, July 25, 2000, pages 1 and 2 - … Why We Stopped Use of the Vaccines, - Atiku:‘THE Vice President, Alhaji Atiku Abubakar has said that the government intervened to stop further administration of Dr. Jeremiah Abalaka’s AIDS vaccine on patients because it has killed more people than it has cured. Speaking at the weekend during a grand reception in his honour at the Nite Shift Coliseum, Lagos, the Vice President said that it was only in Nigeria that “somebody can go and manufacture vaccine without the permission and authorisation of the drug administration of the country before he can begin to administer it on Nigerians.” According to him, the Federal Government had set up a team of medical experts to verify Dr. Abalaka’s claim of successfully manufacturing vaccines to either reduce or cure the scourge which has reached an epidemic level in Africa. The findings of the team indicate that

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Jeremiah O. A. Abalaka

the vaccine could not pass through any acceptable criteria, hence the decision of the Federal Government to order discontinuation of the use of the vaccine. The vice president said that “this man’s drug did not pass through any criteria set. In fact, it has caused more havoc, it has killed people, and it will kill more. That is when the government decided to intervene. Meanwhile, the man is busy administering the vaccine and people are dying.” …’ Note. I sympathize with Nigeria’s Vice President for deliberately choosing to make a public mess of himself, his aides and advisers, believing he was driving the final nail into the coffins of Dr. Abalaka and his HIV vaccines. Though he knows he has no training in medicine, he could not provide himself with knowledgeable aides to advise him. It seems that Nigeria’s VP does not know that when we talk of a new discovery, it means that someone else had not discovered that thing before. My HIV vaccines are new vaccines prepared from human blood. As Vice-President, does he not know that the whole human blood transfusions being carried out in their hundreds everyday in his country are without the permission and authorization of the drug administration of the country before they are being administered on Nigerians and even non-Nigerians? He had not banned their use but he is announcing such a ban of my vaccine that is just human blood extract! If the transfusion of whole human blood does not require permission or authorization from his country’s drug administration before use on human beings, it follows naturally that my HIV vaccines would not require such permission or authorization either. He dragged himself into deeper mess by publicly accusing me of using my HIV vaccines to kill people. If anyone uses, say, a gun to kill people in any country, does that country respond by banning the gun and leaving the user of the gun scot-free? Nigeria’s VP had publicly accused me of murder since July, 2000 but up till now, I have not even been questioned over the murder allegation by the VP! What a country! Additionally, the VP said people were dying from my vaccine but the VP did not mention even one such person. Poor VP! He could not mention one because he did not know of one! Up till today, the VP has not taken any step to ensure I am brought to justice for murder and for violating the country’s drug administration laws! Very pathetic! It is interesting that when a medical practitioner working at the State House Clinic (the Clinic that serves Nigeria’s Presidency and Vice-Presidency) tested positive for HIV in 1999, they shamelessly referred him to me for treatment! Nigeria’s Minister of Health, a top official of the Government of which Atiku Abubakar was VP had called a World Press Conference on 20 July 2000. At that Conference, the minister announced the Nigerian Government’s ban of my HIV vaccines. In response, I took my country’s Government to court over the ban of my HIV vaccines and obtained an injunction against the Government over the ban. I have therefore continued to use my HIV vaccines on willing patients with their written and informed consent up till now.

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Appendix 27 The back page (page 46) of the PUNCH newspaper of Monday, August 14, 2000 carrier an article captioned “Abalaka accuses Atiku, Menakaya of conspiracy … over ban on HIV/AIDS vaccines” in the following words:‘EMBATTLED Abuja-based medical practitioner, who claimed to have found a cure for the dreaded HIV/AIDS disease, Dr. Jeremiah Abalaka, has accused Vice-President Atiku Abubakar and the Minister of Health, Dr. Tim Menakaya, of conspiracy over the ban of his controversial vaccines. In an eight-page reaction sent to Prof. Idris Mohammed, Chairman of the Expert Committee on Verification of Claims for Cure of HIV/AIDS, Abalaka lambasted Atiku and Menakaya, accusing them of conspiracy in the banning of his vaccines. Abalaka called to question, their patriotism and professed concern for HIV/AIDS patients, who are being treated with Abalaka’s vaccines. “If anyone is to talk of patriotism and the interest of HIV/AIDS patients at all, you, Prof. Idris Mohammed and the other members of your clique, namely: Prof. Essien; Prof. I. Akinsete; Dr. Tim Menakaya and Vice-President Atiku, are least qualified to comment on the issue. “For all of you may be anything but certainly not qualified to say you have the interests of HIV/AIDS patients and Nigerians in general in mind at all,” Abalaka said. His reaction came on the heels of a fresh invitation extended to him by the committee for the verification of his claims on the controversial vaccines. The medical practitioner accused members of the Nigerian Academy of Science, which passed a verdict of no-confidence on the vaccines, of having “sold their conscience on the altar of greed.” His words: “Your committee of experts was constituted with my vocal and dishonest critics, just to write out the script already prepared for you by Prof. Akinsete and Dr. Menakaya with the active support of Vice-President Atiku Ababakar.”’ Note. ‘Committee of experts’ they might have been, but experts in what field? Obviously they could not have been experts in HIV vaccine research and development since there are no such fellows in my country, as far as I know. In fact, if, as we have been constantly bombarded, there is no HIV vaccine yet, it follows that the world cannot have any expert in HIV vaccines anywhere. There may be HIV vaccine research experts but until someone develops HIV vaccines, there cannot be any HIV vaccine expert!

Appendix 28 At 1340 hours on 25 August, 2000, I received the following posted letter sent by the author of the letter whom I had never met: ‘15th August, 2000 The Editor The PUNCH (Nig.) Ltd. 1, Kudeti Street

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Jeremiah O. A. Abalaka

Onipetesi Ikeja P.M.B. 21204 Ikeja Lagos. Dear Sir, I will be very grateful if this material, so important to the thousands of HIV infected patients and the Nation at large is put out for publication in your widely read Newspaper. In yesterday’s edition, the back page, I read that Dr Abalaka accused the V. President and the Health Minister of Conspiracy over the ban on the discovery of a vaccine by him for H.I.V. by the Federal Government. Dr Abalaka went on to drop names of the clique behind the Federal Government’s action. I was particularly struck by the inclusion of Prof. (Mrs.) I. Akinsete, a Professor of Hematology. She is my blood sister and the oldest child of my parents. I write as a Christian, a Nigerian Patriot, a Medical Doctor and a man after the health of the generality of Nigerians. I have a Bachelor’s Degree in Immunology from McGill University, Montreal, Canada (1972), MB;B.S. Degree from the UCH Ibadan (1977) and a Post-graduate Diploma in Venereodermatology from the University of Liverpool (1982). I have had three occasions to discuss with my sister, Prof. (Mrs.) I. Akinsete on Dr. J. Abalaka’s vaccine. I discussed with her late last year in November shortly after our mother’s demise; the first of January 2000 at our family residence at Palm-grove, Lagos and in May 2000 after our father’s demise. On all the three occasions, she swore that as long as she remained in Abuja, and as the Chairperson National Action Committee of AIDS, Dr Abalaka’s vaccine would never be approved for treatment by the Government. I asked her why she took that position; she went further, and I quote “How can a man who runs a dirty Hospital and a Surgeon lay claim to a cure for AIDS? I’m a Professor of Hematology and I have no clue whatsoever. This man is after money; Alfa is from the same state and same for Malu (the CAS). They have turned the entire thing into a state issue. Abalaka’s vaccine will definitely not be approved.” I asked her for her reasons, saying even if Dr. Abalaka had mixed sand with water and people were getting better, why not allow him to continue after all AZT was more deadly; that more deaths would be recorded without the vaccine and with AZT than with the use of the vaccine. On all three occasions, she seemed to be uncomfortable with Dr. Abalaka’s vaccines. Coming to the issue at hand, I think the President should realise that he is being led the wrong way. A vaccine that saves four lives out of ten is better than no vaccine at all where the ten are left to die. The Federal Government should reconsider its position in the interest of the H.I.V. infected patients and the Nation at large in view of Prof. (Mrs.) Akinsete’s personal dislike for Dr. Abalaka. (signed) Dr. B. Alaja-Browne 45/47 Karimu Street Surulere-Lagos’

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Note. As far as I know, Nigeria’s President took no action on this letter. If he did, it was not made public. The Punch newspaper to which the letter was addressed carried only an abridged publication that excluded the key issues contained in the letter.

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Appendix 29 Here are the words of the email I sent to the CNN on 3 Aug 2004: “The CNN deserves high marks for reliable news dissemination from any corner of this terrestrial ball. It is rather disappointing that the CNN has been deeply involved in disseminating the false news that effective and safe HIV preventive and curative vaccines are yet to be developed. After years of a solo scientific research from the beginning of 1992, I developed an effective and safe HIV curative vaccine in 1997/8. By 1999, I developed a safe and effective HIV preventive vaccine. Both vaccines have been in use since then. I sent an email to the CNN in 2000 about the development but to my surprise, the CNN turned a deaf ear to the matter! Even though the print and electronic media in Nigeria have been carrying extensive news of the development since 1999, the CNN has ignored the issue! In the interest of the millions of human beings afflicted by the HIV worldwide and in the interest of several more millions in danger of acquiring the HIV, I appeal to the CNN to let the world know that effective and safe HIV vaccines have been developed in Nigeria by a solo scientific researcher before the beginning of this millennium i.e., in 1998/99. Posterity will vindicate the CNN if it effects this correction now. Of course, the CNN is expected to investigate my assertions herein and then report on its findings, if it so chooses. But to ignore it is unfair to humanity. Thank you. Dr. J.O.A. Abalaka Chief Consultant Surgeon/Medical Director Medicrest Specialist Hospital Opposite Demonstration Primary School Near NEPA Substation P. O. Box 382 Gwagwalada- Abuja FCT Nigeria. Tele: +234 9 882 2061 Fax: +234 9 882 2099 August 3, 2004 (0520 gmt)” Note. Up till now, I have received no response from the CNN.

Appendix 30 Subject: Date: From: To:

RE: It's been a while! Wed, 26 Jul 2006 09:06:10 +0100 "Mark Page" Add to Address Book "Jeremiah Abalaka"

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Jeremiah O. A. Abalaka

78 Mark

Page

[email protected]

http://uk.f253.mai

Hi Jeremiah, Yes there has been a problem. We lost all our funding and therefore our staff. Consequently, we have not been able to analyse your sera. Recently, however, we have been successful in getting funds through a grant and I hope to be able to purchase the kit required to do the analysis. This kit is quite expensive but it is the only way we can properly analyse the anti HLA responses. Sorry for the delay and thank you for being patient. It is very frustrating. Best wishes Mark From: Jeremiah Abalaka [mailto:[email protected]] Sent: 25 July 2006 20:11 To: Mark Page Subject: It's been a while! Dear Mark, How are you doing? It's been quite some time since I heard from you. I've been expecting to receive some data results from you. I wonder whether or not any are ready. Or has there been a problem along the line. I look forward to hearing from you, Jeremiah

Appendix 31 Subject: Date: From: To:

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Mark

Results at last!!! Mon, 19 Feb 2007 14:36:22 -0000 "Mark Page" Add to Address Book "Jeremiah Abalaka" Page

[email protected]

http://uk.f230.mai

Hi Jeremiah, At last I have been able to test your samples you sent me. We tested them by ELISA against HLA-DR4 antigen. This antigen was used since it is available and we were running other samples at the same time. I was very surprised to see that all of your samples are reactive against this antigen (see attached Excel graph). Some samples have a lower reactivity of 10 EBV copies / 10 blood cells

Fraction of patients 5 > 10 EBV copies / 10 blood cells

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a)

p=0.022 0.5 0.4 0.3

31/67

0.2 0.1 0.0

4/21 Other donorrecipient pairs

Recipient and donor lacking CCR5Δ32

Figure 5. Association of the CCR5Δ32 deletion mutation with the risk of EBV reactivation after allogeneic HSCT: a) recipient CCR5 genotype and b) donor-recipient polymorphism.

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Association of recipient CCR5 genotype was also valid after adjusting for the other variables known to be associated with the risk of post transplant complications including viral reactivation [61]. The following factors were considered: recipient and donor age and sex, donor-recipient gender relation, type of donor, donor-recipient viral serological status before transplantation, conditioning regimen, diagnosis, GvHD, source of HSC in multivariate logistic regression analysis. In this analysis the presence of CCR5Δ32 allele in the recipient (OR=0.166, 95%CI: 0.034-0.803, p=0.026) was identified as an independent risk factor of EBV reactivation in addition to recipient age (over 25 yrs. old) (OR=1.536, 95%CI: 1.136-2.703, p=0.034). To study the relationship between CCR5 gene expression and EBV reactivation, the viral load and number of CCR5 gene transcripts were assessed at the same time-points 2-3 months following transplantation. CCR5 gene expression was analyzed by a Real-Time PCR technique using SYBR-Green I technology [62] and calculated according to Pfaffl [63] using a relative expression software tool (REST) [64] and given as expression ratio coefficient R. Calculations were performed in relation the expression of beta-actin gene. A greater EBV load (>10 copies/105 cells) was seen in patients with enhanced CCR5 gene expression. It appeared that the CCR5 expression in the group of patients having EBV reactivation was upregulated (by the factor R=25,354) and significantly different from the CCR5 expression in the group of patients lacking EBV reactivation (p=0.024 Pair Wise Fixed Reallocation Radomization Test [63,64], Figure 6). [log2]

Expression ratio Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

(CCR5 in relation to β-actin)

p=0.024 10 5 0 -5 -10

Patients lacking EBV reactivation < EBV-DNA copies / 105 cells

Patients with EBV reactivation > EBV-DNA copies 5 / 10 cells

Figure 6. Relationship between CCR5 gene expression and EBV reactivation in patients after allogeneic HSCT.

These results imply that the presence of the functional CCR5 receptor (assessed either by the lack of the 32-bp deletion within the CCR5 gene or its higher expression) plays a role not only in AIDS and HIV infection but may be also involved in reactivation of other viruses (Table 2), as shown in our study for EBV. We have documented the previously not described associations between polymorphism and expression of the CCR5 gene and EBV load. These data support the theory that a

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patient’s CCR5 genotype may identify individuals less or more prone to EBV reactivation. They might also allow identification of patients at high risk or in the early stage of EBV reactivation after transplantation. This may enable prophylactic treatment or an attempt to cure the infection by administrating anti-CD20 monoclonal antibody or EBV-CTL, or reducing the immunosuppressive therapy. Thus, CCR5 and probably also its ligands might appear to be the novel target molecules of therapeutic intervention in patients undergoing allogeneic HSCT. We also looked at the polymorphism of RANTES/CCL5 - CCR5 ligand (individual data not shown) and found that patients transplanted with donors homozygous for RANTES / CCL5 -403 AA more frequently presented with EBV reactivation [65,66]. These results suggest that increased expression of CCR5 its ligand RANTES/CCL5 facilitate EBV reactivation in patients after HSCT.

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CCR5 IN GRAFT-VERSUS-HOST DISEASE Despite improvements in allogeneic hematopoietic stem cell transplantation, acute GvHD remains a significant problem after transplantation, and it is still a major cause of posttransplant mortality. GvHD is initiated by donor T cells specific against the host antigens. Disease progression is characterized by the differentiation of alloreactive T cells to effector cells leading to tissue damage, recruitment of additional inflammatory cell populations and further cytokine dysregulation [67,68]. The development and evolution of acute GvHD can be conceptualized in three sequential phases to provide a unified perspective on the complex cellular interactions and inflammatory cascades that lead to acute GvHD: (1) activation of the antigen presenting cells (APCs) (2) donor T cell activation, differentiation and migration and (3) effector phase [69]. Although the molecular pathogenesis of GvHD remains to be uncovered, there is general agreement that infiltrating T lymphocytes play a central role. This inflammatory process, in addition to the absolute requirement of donor T cells, involves multiple other innate and adaptive cells and mediators. A characteristic feature of all inflammatory reactions is extensive recruitment of leucocytes to the site of inflammation. This process involves several families of proteins, including pro-inflammatory cytokines, adhesion molecules and chemokines and their receptors [70,71]. The coordinated expression of chemokines and their receptors may be important in the directed migration of alloreactive T cells during GvHD. Chemokines, including macrophage inflammatory proteins MIP-1α, MIP-1β and RANTES (CCL3-5), which are ligands for the CCR5 receptor, are involved in the trafficking of leukocytes in inflammation. These chemokines play a major role in the inflammatory and immune responses that mediate allograft outcome. Their coordinated expression may be important in the directed migration of alloreactive T cells during GvHD. The recent literature has suggested a potential role of CCR5 in a mouse model of GvHD [72]. In this model, acute GvHD was prevented when recruitment of T cells into gut Peyer’s patches was interrupted by disrupting the gene encoding CCR5. Moreover, the presence of the CCR5 deletion mutation has been documented to lead either to complete loss of the

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functional CCR5 receptor or its decreased expression in subjects homozygous or heterozygous for this mutation, respectively [44]. Studies using murine models of acute GvHD have demonstrated the critical role of several chemokines and their receptors (i.e., MIP-1α, MIP-2, monokine induced by IFN-γ (Mig), monocyte chemotactic protein 1 (MCP-1), MCP-3 and CCR5) by directing T-cell infiltration into target tissues during acute GvHD [73-75]. It has been shown that CCR5expressing T lymphocytes are recruited to the liver during acute GvHD in mice [73] while disrupting the gene encoding CCR5 interrupts recruitment of T cells into gut Peyer’s patches and as a result prevents acute GvHD in nonirradiated haploidentical recipients [72]. On the contrary, transferring CCR5-deficient (CCR5-/-) T cells to lethally irradiated mice had been associated with earlier onset and a worsening of GvHD [76]. It has also been documented that polarized human Th1 cells, known to be implicated in the pathomechanism of acute GvHD, preferentially express CXCR3 and CCR5 [40]. In recent human studies, Jaksch et al., [77] who monitored by using quantitative real-time PCR, the expression of 4 chemokine receptors CCR1, CCR2, CCR5, and CXCR3, observed increasing gene-expression levels for CCR5, CXCR3, CCR1, and CCR2 chemokine receptors a few days before acute GvHD was clinically diagnosed. Moreover, Morita et al., [78] showed by immunohistochemical staining the CCR5 expression in infiltrating lymphocytes in cutaneous biopsy specimens taken from patients with chronic GvHD.

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Table 3. Associations of CCR5 gene polymorphisms with the transplant outcome based on literature search (data published 2003-2007). Risk alleles are given in bold. CCR5 gene polymorphism

Transplantation

CCR5Δ32

liver transplantation

CCR5Δ32

renal transplantation

CCR5 59029 A/G

haematopoietic stem cell transplantation heart transplantation

CCR5Δ32

CCR5 59029 CCR5Δ32

renal transplantation

Population (n of individuals studied) German (n=137 pediatric liver graft recipients) Czech (n=436 kidney transplant recipients)

Korean (n=72 recipients and donors) German (n=555 heart transplant recipients) Turkish (n=85 renal transplant patients)

Association

References

no significant correlation between acute graft rejection or chronic graft dysfunction no association with the susceptibility to acute rejection (AR), chronic allograft nephropathy (CAN), and subclinical rejection (SR) as well as graft survival after renal transplantation no association with either recipient or donor CCR5 SNP with acute or chronic GVHD prevalence of CCR5Δ32 polymorphism in long-term (> 7 yrs) survivors of heart transplantation no significant difference in the incidence of rejection among patients possessing or lacking CCR5Δ32, the risk of acute rejection in renal transplantation may be associated with genetic variation in the chemokine receptor genes CCR5 59029

FischerMaas et al., 2008 [102] Brabcova et al., 2007 [103]

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Kim et al., 2007 [79] Hummel et al., 2007 [104] Yigit et al., 2007 [105]

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286

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Table 3. (Continued). CCR5 gene polymorphism

Transplantation

CCR5 E

heart transplantation

CCR5Δ32

haematopoietic stem cell transplantation

CCR5Δ32

cardiac transplantation

CCR5 59029 A/G

renal transplanation

CCR5Δ32

orthotopic liver transplantation

CCR5 59029 A/G

liver transplantation

CCR5Δ32

liver transplantation

CCR5Δ32 CCR5 59029 A/G

renal transplantation

Population (n of individuals studied) Swiss (n=158 heart transplanted patient; on the basis of timing occurrence, acute graft rejection (AR) episodes (grade>or= 3A) were classified in "early" (0-3 months posttransplantation; EAR) or "late" outcomes (4-12 months posttransplantation; LAR) Polish (n= 349 individuals, comprising 186 recipients and 163 donors of allogeneic hematopoietic stem cell transplants) British recipients and corresponding donors

US American (n=244 renal allograft donors) German (n=146 recipients)

US American (n=209 liver transplant recipients) US American (n=207 liver transplant recipients) US American (n=163 renal transplant recipients)

Association

References

none of the polymorphisms were correlated with EAR or LAR in univariate analysis; subjects carrying both the CX3CR1 249I allele and CCR5 No-E haplotypes were significantly at lower risk of experiencing EAR in contrast subjects carrying both the CCR5 E haplotype and the RANTES -403A allele were significantly at higher risk to develop LAR

Simeoni et al., 2007 [106]

lower incidence of acute GvHD in recipients carrying the CCR5Delta32 allele; acute GvHD symptoms were not observed in any of the recipients carrying the CCR5Δ32 allele transplanted from donors with this deletion mutation no correlation between recipient genotype and outcome following transplantation; a significant correlation between donor genotype and mortality in patients transplanted for a nonischemic condition association with acute rejection

BoguniaKubik et al., 2006 [15]

increased occurrence of ischemictype biliary lesions; reduction in 5-year patient survival no association with the incidence of acute rejection and long-term liver graft survival no association with the risk for acute rejection or graft survival significant reductions in risk of acute renal transplant rejection in recipients who were homozygous for the 59029-A allele; no significant differences in the incidence of rejection among patients stratified as with or without CCR5Δ32

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Fildes et al., 2005 [107]

Hoffmann et al., 2004 [108] Moench et al., 2004 [109] Schröppel et al., 2002 [110] Schröppel et al., 2002a [111] Abdi et al., 2002 [112]

Emerging roles of SDF-1α -Cxcr4 axis in vertebrate development

287

CCR5Δ32 POLYMORPHISM AND THE RISK OF GRAFT-VERSUS-HOST DISEASE AFTER ALLOGENEIC HSCT In our study we investigated the relationship between the incidence and severity of acute or chronic GvHD associated with the presence of a defective CCR5 expression, through the 32-bp deletion mutation in the recipients and donors of allogeneic haematopoeitc stem cell transplants [15]. We found a significant correlation between the presence of the CCR5Δ32 allele in the recipients and a lower risk of acute GvHD and observed a lack of acute GvHD symptoms in patients having the CCR5Δ32 allele transplanted with donors carrying this deletion mutation. To our knowledge this was the first study in humans describing the association between the CCR5 gene polymorphism and HSCT outcome [15], although there have been several studies which analysed the role of CCR5 gene polymorphism in relation to the outcome of organ transplantation (summarized in Table 3). Moreover, more recently Kim et al., (2007) [79] reported no association of either recipient or donor CCR5 59029 A/G polymorphism with acute or chronic GvHD after transplantation of haematopoietic stem cells in Koreans. CCR5 contributes to the alloimmune response following solid organ transplantation. In individuals homozygous for the CCR5Δ32 mutation, the receptor is inactive and lymphocyte recruitment and leukocyte trafficking during rejection are inhibited. A significant improvement in graft survival following renal transplantation has been observed in homozygous CCR5Δ32 patients, although conflicting data exist. In our study, the presence of the CCR5Δ32 deletion mutation was found to be associated with a lower susceptibility to acute GvHD. Recipients carrying the CCR5Δ32 allele (associated with defective CCR5 expression) had acute GvHD (grades I-IV) less frequently as compared to patients lacking the CCR5 deletion mutation (11/35 vs. 76/151, p=0.033, Figure 7a). This relationship was also seen for grades II-IV acute GvHD (5/35 vs. 43/151, p=0.060). The highest grades of GvHD were observed in recipients lacking CCR5Δ32 allele. Sixteen out of 17 recipients with grades III-IV acute GvHD were homozygous for the wild type allele. a)

b)

0.4 76/151 0.3 0.2

11/35

0.1 0.0

Patients Patients carrying lacking CCR5Δ32

p=0.002 Fraction of patient with grade I-IV aGvHD

Fraction of patients with grade I-IV aGvHD

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p=0.033 0.5

0.5 0.4 0.3

70/151

0.2 0.1 0.0

0/11 Recipient and donor carrying CCR5Δ32

Other donorrecipient pairs

Figure 7. Association of the CCR5Δ32 deletion mutation with the risk of acute graft-versus-host disease after allogeneic HSCT: a) recipient CCR5 genotype and b) donor-recipient polymorphism.

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This protective role of the recipient CCR5Δ32 allele was confirmed by multivariate logistic regression analyses for acute GvHD. The following factors were considered: donor and recipient sex, recipient age, donor-recipient gender, intensity of conditioning regimen (myeloablative vs non-myeloablative), diagnosis (haematological malignancies vs others), transplant material (bone marrow - BM vs peripheral blood progenitor cells - PBPC), GvHD prophylaxis (CsA vs multiagent), transplantation setting (alternative vs sibling donor). Following logistic regression analysis, 3 variables appeared to be significantly associated with the risk of developing acute GvHD. The presence of CCR5 deletion mutation was found to be associated with a lower risk of developing acute GvHD (OD=0.391, 95%CI=0.1740.880, p=0.023). Transplantation from alternative donor (OD=2.007, 95%CI=1.078-3.736, p=0.028), recipient age (over 35 yrs) (OD=2.117, 95%CI=1.032-4.345, p=0.041) and myeloablative conditioning regimen (OD=2.235, 95%CI=1.175-4.252, p=0.014) were found as factors associated with an increased risk of acute GvHD (grades I-IV). Similar correlations were observed with multivariate analysis for grades II-IV acute GvHD. This analysis confirmed the contribution of recipient CCR5 polymorphism to the risk of developing acute GvHD. Although some direct associations of donor genotype with the risk of the incidence of GvHD might be expected from previous animal studies [72,76,80], we observed no relationships between the presence of the CCR5Δ32 allele in donors and the transplant outcome (development of acute GvHD - independently of the severity of the disease; manifestation of chronic GvHD independently of the “limited / extensive” classification; the incidence of relapse or the fatal outcome (individual data not shown)). However, additional analysis of different combinations of donor recipient CCR5 genotypes demonstrated that the presence of the CCR5 deletion mutation in recipients and their donors of allogeneic HSCT plays the most protective role. None of 11 recipients carrying the CCR5Δ32 allele transplanted with donor having the CCR5Δ32 allele developed acute GvHD (grades I-IV) as compared to 70 out of 151 donor-recipient pairs carrying the other combinations of CCR5 alleles (0.00 vs 0.46, p=0.002, Figure 7b). More severe acute GvHD (grades III or IV) was seen only in recipients transplanted with donors carrying wild type genotype (lacking the CCR5 deletion mutation). Thus the protective effect of the CCR5Δ32 deletion mutation was especially seen in recipients transplanted with donors carrying the CCR5Δ32 allele. The association of recipient CCR5Δ32 allele was an unexpected observation regarding the recent data from the studies in the murine models of GvHD [72,76,80] suggesting that we could rather expect some associations with donor CCR5 genotype than those of transplant recipients. However, they also indicate that the role of CCR5 in allogeneic bone marrow transplants and GvHD is quite complex as the absence of donor expression of CCR5 on T cells ameliorates GvHD in models using no conditioning of the recipient [72] while, on the other hand, in a murine transplant model with intensive conditioning, the overall effect of absent CCR5 expression on donor cells results in greater incidence/severity of GvHD [76,80] and donor T-cell expansion [80] An interesting, although not significant, relationship was seen between the incidence of GvHD and pre-transplant conditioning regimen. Donors having one wild type allele induced

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more GvHD in recipients on myeloablative conditioning regimen as compared to recipients on non-myeloablative conditioning and those who did not receive any conditioning regimen (0.29 vs. 0.07, ns). This observation concurs with the results of Wysocki et al., [76]. Study of Wysocki et al., [76] showed that transferring CCR5-deficient (CCR5-/-) T cells to lethally irradiated mice had been associated with earlier onset and a worsening of GvHD. Welniak et al., [80] suggested that transplantation of full MHC-mismatched donor bone marrow and splenocytes from CCR5 knockout mice might result in higher IFN-γ and TNF-α production by recovered T cells and better proliferation to a T-cell mitogen with a lower expansion of CD8+ T cells, indicating that CCR5 plays a role in down regulating donor alloreactive CD8+ T-cell expansion. It is difficult to explain the observed in our study protective effect of the lack of functional chemokine receptor on recipient cells. Our study suggests that also expression of CCR5 on recipient cells, especially early after transplantation, may play a role in the alloresponse leading to GvHD. Interestingly, the recent studies in organ transplant recipients have suggested that expression of CCR5 may play an important role in directing T cells into allografts to mediate acute rejection. The lack of functional CCR5 on recipient cells has been found to be associated with better transplantation outcome. For example, the prolonged survival of cardiac allografts was reported in recipients either lacking CCR5 or treated with CCR5 neutralizing monoclonal antibody [81]. In clinical renal transplantation, the presence of a homozygous mutation encoding non-functional CCR5 in recipients was associated with decreases in acute rejection and better graft outcomes as compared to the recipients expressing functional receptor [82]. Our results would suggest that also in HSCT a lack of functional CCR5 on recipient cells may play a protective role. It could be speculated that enhanced migration of recipient T cells lacking functional CCR5 (carrying the CCR5Δ32 allele) to lymphoid tissue in response to proinflammatory chemokines induced by conditioning regimen (irradiation) may limit T cell engraftment and expansion. Indeed the study of Wysocki et al., [76] showed that T cells lacking CCR5 had enhanced migration to CXCL10 (the IFN-inducible CXCR3 ligand) in irradiated recipients. In addition, it was documented that CD4+CD25+ T regulatory cells (T regs), whose presence is associated with a lower the risk of developing acute GvHD, need CCR5 to function [83]. All these results, from the studies in mice and the present one in humans, indicate that the role of CCR5 in allogeneic bone marrow transplants and GvHD is more complex than initially thought. Moreover, a direct association between levels of CCR5 and differentiation of monocytes to macrophages has been documented [84]. It has been also found that cross-linking of CCR5 on monocytes leads to activation and differentiation of monocytes into dendritic cells while following the cross-linking of CCR5, monocytes synthesize high levels of M-CSF, RANTES, MIP-1α, and MIP-1ß associated with a readily detectable down modulation of CD14, CD4, CCR5, and CXCR4 expression [85]. Thus it would be of interest to look at the changes in CCR5 expression at different time points post– transplant, during acute GvHD, in the different cell populations including not only lymphocytes, but also those that might function as professional antigen presenting cells such as monocytes/macrophages. However, this remains to be determined.

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GENERAL SUMMARY AND CONCLUSIONS The data presented and discussed in this chapter support the theory that CCR5 genotype may be of prognostic value for transplant outcome. The ideal predictive markers for viral complications and GvHD are likely to have certain characteristic and would be most useful if assessable pre-transplant. Pre-transplant risk assessment would allow the patient to make a better informed decision about their therapeutic options and possibly allow physicians to modify GVHD prophylaxis regimens or antiviral therapy in those patients at the lowest or highest risk of these complications. It is possible that both the genomics and expression of CCR5 may provide additional predictive factors for the development of a prognostic score for individual patients based on their clinical and laboratory characteristics. These results significantly contribute to the studies highlighting the potential importance of non-HLA polymorphisms in HSCT (i.e. [1-4] and indicate that non-HLA genotyping may be useful to identify patients at the highest risk of complications. Thus, CCR5 and probably also its ligands might be the novel target molecules of therapeutic intervention in patients undergoing allogeneic HSCT. However, the results of the effect of CCR5 gene polymorphism need to be confirmed in other patient-donor pairs to assess whether analysis of CCR5 gene polymorphism could be included for standard patient-donor genotyping to complement traditional histocompatibility testing, and increase the ability to predict the risk of transplantrelated complications.

ACKNOWLEDGEMENTS This work was supported by grants no. 2 PO5B 085 28 and NN 402 193335 from the Polish Ministry of Science and Higher Education (MNiSW, Poland).

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[68] Lichtman, AH, Krenger, W, Ferrara, JLM. Cytokine Networks. In Ferrara, JLM, Deeg, HJ, Burakoff, SJ Ed. Graft versus host disease, M. Dekker, Inc.: New York. 1997, p. 179-218. [69] Ferrara, JL, Reddy, P. Pathophysiology of graft-versus-host disease. Semin Hematol, 2006, 43, 3-10. [70] Gouwy, M, Struyf, S, Proost, P, Van Damme, J. Synergy in cytokine and chemokine networks amplifies the inflammatory response. Cytokine Growth Factor Rev, 2005, 16, 561-580. [71] Coelho, AL, Hogaboam, CM, Kunkel, SL. Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev, 2005, 16, 553-560. [72] Murai, M, Yoneyama, H, Ezaki, T, Suematsu, M, Terashima, Y, Harada, A, Hamada, H, Asakura, H, Ishikawa, H, Matsushima, K. Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol, 2003, 4, 154-160. [73] Murai, M, Yoneyama, H, Harada, A, Yi, Z, Vestergaard, C, Guo, B, Suzuki, K, Asakura, H, Matsushima, K. Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest, 1999, 104, 49-57. [74] Serody, JS, Burkett, SE, Panoskaltsis-Mortari, A, Ng-Cashin, J, McMahon, E, Matsushima, GK, Lira, SA, Cook, DN, Blazar, BR. T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8(+) T cells to the liver, lung, and spleen during graft-versus-host disease. Blood, 2000, 96, 2973-2980. [75] New, JY, Li, B, Koh, WP, Ng, HK, Tan, SY, Yap, EH, Chan, SH, Hu, HZ. T cell infiltration and chemokine expression: relevance to the disease localization in murine graft-versus-host disease. Bone Marrow Transplant, 2002, 29, 979-986. [76] Wysocki, CA, Burkett, SB, Panoskaltsis-Mortari, A, Kirby, SL, Luster, AD, McKinnon, K, Blazar, BR, Serody, JS. Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J Immunol, 2004, 173, 845-854. [77] Jaksch, M, Remberger, M, Mattsson, J. Increased gene expression of chemokine receptors is correlated with acute graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant, 2005, 11, 280-287. [78] Morita, NI, Matsumura, Y, Morita, K, Miyachi, Y. Expression of CCR5 in graft-versushost disease (GVHD) of the skin: immunohistochemical staining of 38 cases. J Dermatol, 2007, 34, 254-257. [79] Kim, DH, Jung, HD, Lee, NY, Sohn, SK. Single nucleotide polymorphism of CC chemokine ligand 5 promoter gene in recipients may predict the risk of chronic graftversus-host disease and its severity after allogeneic transplantation. Transplantation, 2007, 84, 917-925. [80] Welniak, LA, Wang, Z, Sun, K, Kuziel, W, Anver, MR, Blazar, BR, Murphy, WJ. An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease. Exp Hematol, 2004, 32, 318-324.

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[81] Gao, W, Faia, KL, Csizmadia, V, Smiley, ST, Soler, D, King, JA, Danoff, TM, Hancock, WW. Beneficial effects of targeting CCR5 in allograft recipients. Transplantation, 2001, 72, 1199-1205. [82] Fischereder, M, Luckow, B, Hocher, B, Wuthrich, RP, Rothenpieler, U, Schneeberger, H, Panzer, U, Stahl, RA, Hauser, IA, Budde, K, Neumayer, H, Kramer, BK, Land, W, Schlondorff, D. CC chemokine receptor 5 and renal-transplant survival. Lancet, 2001, 357, 1758-1761. [83] Wysocki, CA, Jiang, Q, Panoskaltsis-Mortari, A, Taylor, PA, McKinnon, KP, Su, L, Blazar, BR, Serody, JS. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood, 2005, 106, 3300-3307. [84] Tuttle, DL, Harrison, JK, Anders, C, Sleasman, JW, Goodenow, MM. Expression of CCR5 increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1. J Virol, 1998, 72, 4962-4969. [85] Nimura, F, Zhang, LF, Okuma, K, Tanaka, R, Sunakawa, H, Yamamoto, N, Tanaka, Y. Cross-linking cell surface chemokine receptors leads to isolation, activation, and differentiation of monocytes into potent dendritic cells. Exp Biol Med (Maywood), 2006, 231, 431-443. [86] Gonzalez, E, Dhanda, R, Bamshad, M, Mummidi, S, Geevarghese, R, Catano, G, Anderson, SA, Walter, EA, Stephan, KT, Hammer, MF, Mangano, A, Sen, L, Clark, RA, Ahuja, SS, Dolan, MJ, Ahuja, SK. Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci U S A, 2001, 98, 5199-5204. [87] Lim, JK, Louie, CY, Glaser, C, Jean, C, Johnson, B, Johnson, H, McDermott, DH, Murphy, PM. Genetic Deficiency of Chemokine Receptor CCR5 Is a Strong Risk Factor for Symptomatic West Nile Virus Infection: A Meta-Analysis of 4 Cohorts in the US Epidemic. J Infect Dis, 2008, 197, 262-265. [88] Cheong, JY, Cho, SW, Choi, JY, Lee, JA, Kim, MH, Lee, JE, Hahm, KB, Kim, JH. RANTES, MCP-1, CCR2, CCR5, CXCR1 and CXCR4 gene polymorphisms are not associated with the outcome of hepatitis B virus infection: results from a large scale single ethnic population. J Korean Med Sci, 2007, 22, 529-535. [89] Thio, CL, Astemborski, J, Bashirova, A, Mosbruger, T, Greer, S, Witt, MD, Goedert, JJ, Hilgartner, M, Majeske, A, O'Brien, SJ, Thomas, DL, Carrington, M. Genetic protection against hepatitis B virus conferred by CCR5Delta32: Evidence that CCR5 contributes to viral persistence. J Virol, 2007, 81, 441-445. [90] Ahn, SH, Kim do, Y, Chang, HY, Hong, SP, Shin, JS, Kim, YS, Kim, H, Kim, JK, Paik, YH, Lee, KS, Chon, CY, Moon, YM, Han, KH. Association of genetic variations in CCR5 and its ligand, RANTES with clearance of hepatitis B virus in Korea. J Med Virol, 2006, 78, 1564-1571. [91] Goyal, A, Suneetha, PV, Kumar, GT, Shukla, DK, Arora, N, Sarin, SK. CCR5Delta32 mutation does not influence the susceptibility to HCV infection, severity of liver disease and response to therapy in patients with chronic hepatitis C. World J Gastroenterol, 2006, 12, 4721-4726.

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[92] Loeffler, J, Steffens, M, Arlt, EM, Toliat, MR, Mezger, M, Suk, A, Wienker, TF, Hebart, H, Nurnberg, P, Boeckh, M, Ljungman, P, Trenschel, R, Einsele, H. Polymorphisms in the genes encoding chemokine receptor 5, interleukin-10, and monocyte chemoattractant protein 1 contribute to cytomegalovirus reactivation and disease after allogeneic stem cell transplantation. J Clin Microbiol, 2006, 44, 18471850. [93] Suneetha, PV, Sarin, SK, Goyal, A, Kumar, GT, Shukla, DK, Hissar, S. Association between vitamin D receptor, CCR5, TNF-alpha and TNF-beta gene polymorphisms and HBV infection and severity of liver disease. J Hepatol, 2006, 44, 856-863. [94] Glass, WG, McDermott, DH, Lim, JK, Lekhong, S, Yu, SF, Frank, WA, Pape, J, Cheshier, RC, Murphy, PM. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med, 2006, 203, 35-40. [95] Chang, HY, Ahn, SH, Kim, DY, Shin, JS, Kim, YS, Hong, SP, Chung, HJ, Kim, SO, Yoo, WD, Han, KH. [Association between CCR5 promoter polymorphisms and hepatitis B virus infection]. Korean J Hepatol, 2005, 11, 116-124. [96] Goulding, C, McManus, R, Murphy, A, MacDonald, G, Barrett, S, Crowe, J, Hegarty, J, McKiernan, S, Kelleher, D. The CCR5-delta32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source. Gut, 2005, 54, 11571161. [97] Wald, O, Pappo, O, Ari, ZB, Azzaria, E, Wiess, ID, Gafnovitch, I, Wald, H, Spengler, U, Galun, E, Peled, A. The CCR5Delta32 allele is associated with reduced liver inflammation in hepatitis C virus infection. Eur J Immunogenet, 2004, 31, 249-252. [98] Ruiz-Ferrer, M, Barroso, N, Antinolo, G, Aguilar-Reina, J. Analysis of CCR5-Delta 32 and CCR2-V64I polymorphisms in a cohort of Spanish HCV patients using real-time polymerase chain reaction and fluorescence resonance energy transfer technologies. J Viral Hepat, 2004, 11, 319-323. [99] Wasmuth, HE, Werth, A, Mueller, T, Berg, T, Dietrich, CG, Geier, A, Schirin-Sokhan, R, Gartung, C, Lorenzen, J, Matern, S, Lammert, F. CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia. J Mol Med, 2004, 82, 64-69. [100] Hellier, S, Frodsham, AJ, Hennig, BJ, Klenerman, P, Knapp, S, Ramaley, P, Satsangi, J, Wright, M, Zhang, L, Thomas, HC, Thursz, M, Hill, AV. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. Hepatology, 2003, 38, 1468-1476. [101] Promrat, K, McDermott, DH, Gonzalez, CM, Kleiner, DE, Koziol, DE, Lessie, M, Merrell, M, Soza, A, Heller, T, Ghany, M, Park, Y, Alter, HJ Hoofnagle, JH, Murphy, PM; Liang, TJ. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology, 2003, 124, 352-360. [102] Fischer-Maas, L, Schneppenheim, R, Oyen, F, Grabhorn, E, Richter, A, Fischer, L, Ganschow, R. Analysis of the CC chemokine receptor 5Delta32 polymorphism in pediatric liver transplant recipients. Pediatr Transplant, 2008, aheadofprint.

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[103] Brabcova, I, Petrasek, J, Hribova, P, Hyklova, K, Bartosova, K, Lacha, J, Viklicky, O. Genetic variability of major inflammatory mediators has no impact on the outcome of kidney transplantation. Transplantation, 2007, 84, 1037-1044. [104] Hummel, M, Bara, C, Hirt, S, Haverich, A, Hetzer, R. Prevalence of CCR5Delta32 polymorphism in long-term survivors of heart transplantation. Transpl Immunol, 2007, 17, 223-226. [105] Yigit, B, Bozkurt, N, Berber, I, Titiz, I, Isbir, T. Analysis of CC chemokine receptor 5 and 2 polymorphisms and renal transplant survival. Cell Biochem Funct, 2007, 25, 423426. [106] Simeoni, E, Vassalli, G, Seydoux, C, Ramsay, D, Noll, G, von Segesser, LK, Fleury, S. CCR5, RANTES and CX3CR1 polymorphisms: possible genetic links with acute heart rejection. Transplantation, 2005, 80, 1309-1315. [107] Fildes, JE, Walker, AH, Howlett, R, Bittar, MN, Hutchinson, IV, Leonard, CT, Yonan, N. Donor CCR5 Delta32 polymorphism and outcome following cardiac transplantation. Transplant Proc, 2005, 37, 2247-2249. [108] Hoffmann, S, Park, J, Jacobson, LM, Muehrer, RJ, Lorentzen, D, Kleiner, D, Becker, YT, Hullett, DA, Mannon, R, Kirk, AD, Becker, BN. Donor genomics influence graft events: the effect of donor polymorphisms on acute rejection and chronic allograft nephropathy. Kidney Int, 2004, 66, 1686-1693. [109] Moench, C, Uhrig, A, Lohse, AW, Otto, G. CC chemokine receptor 5delta32 polymorphism-a risk factor for ischemic-type biliary lesions following orthotopic liver transplantation. Liver Transpl, 2004, 10, 434-439. [110] Schroppel, B, Fischereder, M, Lin, M, Marder, B, Schiano, T, Kramer, BK, Murphy, B. Analysis of gene polymorphisms in the regulatory region of MCP-1, RANTES, and CCR5 in liver transplant recipients. J Clin Immunol, 2002, 22, 381-385. [111] Schroppel, B, Fischereder, M, Ashkar, R, Lin, M, Kramer, BK, Mardera, B, Schiano, T, Murphy, B. The impact of polymorphisms in chemokine and chemokine receptors on outcomes in liver transplantation. Am J Transplant, 2002, 2, 640-645. [112] Abdi, R, Tran, TB, Sahagun-Ruiz, A, Murphy, PM, Brenner, BM, Milford, EL, McDermott, DH. Chemokine receptor polymorphism and risk of acute rejection in human renal transplantation. J Am Soc Nephrol, 2002, 13, 754-758.

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In: AIDS Vaccines, HIV Receptors and AIDS Research ISBN 978-1-60692-074-9 Editor: Lawrence B. Kendow © 2008 Nova Science Publishers, Inc.

Chapter 8

EMERGING ROLES OF SDF-1α -CXCR4 AXIS IN VERTEBRATE DEVELOPMENT Vladimir Korzh1 and Shang-Wei Chong2 1

Laboratory of Fish Developmental Biology, Institute of Molecular and Cell Biology, Singapore; 2 Laboratory of Developmental Signaling and Patterning, Institute of Molecular and Cell Biology, Singapore.

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ABSTRACT The CXC chemokine receptor CXCR4 is well-known as the docking site of the HIV1 virus in the membrane of the host cell. Although CXCR4 binds a single ligand, SDF1α, it plays multiple roles in the development of vertebrates. In rodents, the expression pattern of the single CXCR4 gene is very dynamic reflecting the many functions of this chemokine receptor. In teleost genomes, both chemokine receptor Cxcr4 and its ligand are divided between two duplicated cxcr4 and sdf1α genes as a consequence of the species specific process called subfunctionalization, facilitating the analysis of specific gene functions in different cell lineages, tissues and organs during development. Recently, several zebrafish mutants that affect genes encoding components of the SDF1α-Cxcr4 signalling system became available. In combination with results from gene knockdown experiments, these mutants shed light on the roles of SDF1α-Cxcr4 signaling during cell migration and cell fate determination of various cell lineages. This short review will summarize the recent progress in deciphering the developmental roles of SDF1α-Cxcr4, focusing mainly on the findings in teleosts.

Keywords: chemotaxis, CXCR4, SDF1, zebrafish, cell migration, cell fate determination.

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INTRODUCTION Development of the overall body structure during gastrulation and organ formation during subsequent stages is characterized by cellular traffic as one of the main shape-giving mechanisms. For example, during neural development neural progenitor cells migrate from the inner ventricular layer to the outer pial surface of the neural tube and neural crest cells originating from the dorsal neural tube migrate and colonize many different tissues, including cranial skeleton and the peripheral nervous system. Elsewhere, the primary germ cells travel on a complex route through the embryo to populate the gonads. Myoblasts also migrate from somites into limb buds to form muscles, underscoring that migratory behavior is found in the cells of all germ layers including the mesoderm. In many instances, migration towards specific targets appears to be driven by chemotaxis, which is characterized by expression of a ligand (or chemokine) by target cells and a chemokine receptor by migrating cells. Directionally migrating cells exhibit clear morphological polarity, which is often manifested in an elongated cell shape and widespread protrusive activity at the cell front. Chemotactic cells are able to discriminate among extracellular chemical signals and guide their movement in response to a concentration gradient of signal. Eukaryotic cells are about 10–20 μm in diameter. By sensing the difference in chemoattractant concentration at the opposite ends of the cell, they move along the gradient of chemoattractant towards their targets. Such characteristic chemotatic behavior of cells is very well studied in Dictyostelium amoebae and mammalian leukocytes where changes in intracellular Ca2+ may be implicated during chemotaxis (Devreotes and Zigmond 1988; Newell et al., 1990; Charest and Firtel 2006). The chemokine receptor CXCR4 (CXC chemokine receptor) belongs to the superfamily of seven- transmembrane domain, G-protein coupled receptors. CXCR4 is well-known since it is used by HIV-1 for binding to the cell membrane and infection of CD4+ T cells (reviewed in Bleul et al., 1996 ). CXCR4 is a specific alpha-chemokine receptor that interacts with its ligand SDF-1α (stromal-derived-factor-1), which is also known as chemokine (C-X-C motif) ligand 12 (CXCL12). This interaction stimulates turnover of CXCR4 that can be regulated by various means. One factor that contributes to this turnover is Rab5 (Venkatesan et al., 2003). Other factors that regulate CXCR4 internalization include the carboxyl-terminal residues/phosphorylation sites, di-Leucine motifs, intracellular loops and dynamin (Cheng et al., 2000; Orsini et al., 1999; Signoret et al., 1997). Further modifications to CXCR4 include ubiquitination resulting in receptor endocytosis and lysosomal degradation (Marchese and Benovic 2001). These modifications have important implications to chemotaxis and signaling. During mammalian development, the expression patterns of Cxcr4 and SDF-1α change rapidly, illustrating the multitude and dynamics of migratory events under control of this receptor-ligand pair (McGrath et al., 1999; Stumm et al., 2003). The SDF1α-Cxcr4-signaling system has been implicated in regulation of migration of lymphocytes, neuronal cells in the cerebellum and heart, hypaxial muscles. It is also involved in formation of axonal territory of motor neurons or mediation of molecular interaction between precursors of projection neurons and invading interneurons during corticogenesis, etc (Lieberam et al., 2005; Tachibana et al., 1998; Tiveron et al., 2006; Zou et al., 1998). Due to these multiple functions and the dynamics of the expression of receptor and ligand in mammals, it has been difficult to

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assign specific developmental roles to particular aspects of the complex pattern of expression of the two genes. As a consequence, the phenotype of mouse mutants deficient in these genes is also complex. The developmental roles of mammalian CXCR4 and SDF-1α appear to be split between the two pairs of related zebrafish genes, cxcr4a/cxcr4b and sdf1a/sdf1b. In most but not all cell lineages, two zebrafish genes of each pair have mutually exclusive patterns of expression. For example, the expression of cxcr4b in the lateral mesoderm starts early, while that of cxcr4a is delayed and more restricted, suggesting slightly different developmental roles of the two paralogous genes in derivatives of the lateral mesoderm (Chong et al., 2001). In addition, it seems that in embryonic zebrafish, the expression patterns of each of the duplicated genes once established are maintained for some time in contrast to that in mammals, where these expression patterns are relatively more dynamic. This could be a direct result of gene duplication followed by their subfunctionalization resulting in loss of some specific functions for each of the genes. Owing to such subfunctionalization of the developmental roles of Cxcr4a and b, zebrafish researchers were able to unravel novel roles of SDF1α-Cxcr4 signaling in cell migration and differentiation that went unnoticed in mammalian studies. For instance, the expression pattern of cxcr4b resembles a combination of the expression patterns of two bHLH genes, one of which is expressed in the central nervous system (CNS) and the other in somites - embryonic blocks of lateral mesoderm giving rise to axial musculature. Experimental evidence already illustrated a regulatory link between Cxcr4 and bHLH genes during myogenesis (see below) and it could be logically hypothesized that Cxcr4s may play more general roles in developmental events of cell determination/differentiation involving bHLH proteins. In this review we will consider examples of the two developmental processes involving SDF1α-CXCR4 axis – cell determination/differentiation and migration.

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Migration of Primary Germ Cells A useful in vivo model for studying cell polarization and guided migration is that of primordial germ cell (PGC) migration (Raz, 2003; Raz and Reichman-Fried, 2006). PGCs are predecessors of germ cells and these have genetic material that may be passed on to the next generation. In zebrafish, these migrating cells are specified at four different locations corresponding to positions of the plane of cell division of the first four blastomeres. During subsequent development, the anterior PGCs migrate posterior towards their final location in germinal ridges. At the start of gastrulation, PGCs are found close to the blastoderm margin. By the tailbud stage, these cells align along the anterior border of the trunk mesoderm or the pronephros at the lateral border of the mesoderm. PGCs express CXCR4b and directionally migrate towards prospective germinal ridges which primordium expresses the ligand SDF-1α (Blaser et al., 2005; Doitsidou et al., 2002; Knaut et al., 2003; Reichman-Fried et al., 2004). To reach germinal ridges, the posterior PGCs migrate anteriorly (Weidinger et al., 1999). While internalization and the control over signaling intensity of receptors are dispensable for cell motility and directional sensing they are essential for fine-tuning of migration in vivo, allowing arrival of zebrafish PGCs to the

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germinal ridge, where the gonad develops (Minina et al., 2007). The serine amino acid residue within the most distal region of the cytoplasmic tail of CXCR4 is required for internalization of this receptor. This residue is conserved between fish and human. A rise in calcium levels is one of the earliest events after activation of CXCR4 by SDF-1α (Oberlin et al., 1996; Oh et al., 2002), and such an increase was shown to be important for proper PGC migration in zebrafish, where both the chemokine-receptor internalization and certain level of SDF-1α signaling are necessary for proper chemotaxis of germ cells (Blaser et al., 2005; Minina et al., 2007). In the absence of Cxcr4b caused by morpholino knockdown or ody mutation, instead of forming a tight group of PGCs, these cells become scattered over a large area (Doitsidou et al., 2002; Knaut et al., 2003). Recently, it has been found that during PGC migration another receptor of SDF-1α, the nonsignaling receptor CXCR7 functions as a sink for SDF1a and this activity probably maintains the steepness of the SDF-1α gradient (Boldajipur et al., 2008).

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Migration of the Lateral Line Primordium The lateral line of the zebrafish is comprised of a set of discrete mechanosensory organs known as the neuromasts, which are arranged in a well-defined pattern along the A-P axis (Dambly-Chaudière et al., 2003). These organs are deposited as a consequence of the directed migration of a primordium. The development of the posterior lateral line (PLL) has been studied in amphibians and was shown to involve the formation of a migrating primodium that deposits small groups of cells, each one a prospective neuromast (Harrison, 1904; Northcutt et al., 1994). In zebrafish, the posterior lateral line (PLL) placode forms just posterior to the otic vesicle. The zebrafish PLL primodium (PLLP), a cohesive cohort of over 100 cells delaminates at about 18hpf. Within a couple of hours, the PLLP starts to migrate posteriorly along the horizontal myoseptum and reaches the tail tip at about 40 hpf. During this migration process, axons connecting neuromasts extend from the PLL ganglion and their growth cones migrate within the PLLP (Metcalfe et al., 1985; Gilmour et al., 2004). Migration of the zebrafish PLLP is guided by Sdf1a-Cxcr4 signaling. cxcr4b is expressed by the PLLP, which route of migration - the horizontal myoseptum expresses sdf1a and along its way deposits clusters of cells forming neuromasts. It has been shown that the cells undergo the coordinated movements within the migrating PLLP, which are abnormal in various mutants affecting the formation of the notochord (eg. Figure 1) or components of SDF1α-Cxcr4 axis [e.g., odysseus (ody) deficient in Cxcr4b], resulting in inability of the primodium to migrate correctly (Chong et al., 2001; Gilmour et al., 2004; Haas and Gilmour, 2006). It was shown that the specific Cxcr4b activity is only required in cells at the leading edge of PLLP, raising the question of what controls cell behavior within trailing regions. A recent analysis of the first mutant in zebrafish Sdf-1a (medusa) demonstrated that its phenotype is stronger than that caused by a null mutation ody affecting Cxcr4b and indicated a possibility that other receptors interacting with SDF-1α could be involved in developmental events taking place in the lateral line (Valentin et al., 2007). To support this idea, the orphan receptor RDC1 was shown to interact with SDF-1α in vitro and as a result was renamed as CXCR7 (Balabanian et al., 2005). Zebrafish cxcr7 has

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been cloned and its restricted expression was found in trailing cells of PLLP. Morpholino knockdown of Cxcr7 resulted in a novel phenotype in which the migration of trailing cells was specifically affected, causing the primordium to be stretched. This defect was rescued by the reintroduction of wild-type cells specifically amongst trailing cells of the primordium. So, it seems that Cxcr4b and Cxcr7 act independently to regulate migration of PLLP as a group of cells. A single extrinsic guidance cue, SDF-1α, directly controls the migration of both leading and trailing edges of a tissue through the activation of these two receptors (Valentin et al., 2007). It is possible that once vertebrates inherited the basic mechanism regulating cell migration through changes in intracellular Ca2+ that developed in more primitive organisms, they added to this mechanism several new levels of regulation. It remains unclear whether Cxcr7 acts as a sink for SDF-1α in the lateral line primordium as it does in the PGCs (Boldajipur et al., 2008; Valentin et al., 2007).

Figure 1. Migration defect of the posterior lateral line primodium. (A,B) cxcr4b is expressed by the posterior lateral line primodium (PLLP) in 30hpf control and floating head (flh) embryos deficient in the notochord and the SDF-1-expressing horizontal myoseptum. (A) During its migration in control embryos along the horizontal myoseptum PLLP deposits cells forming neuromasts. In flh embryos, where the horizontal myoseptum and its SDF-1 expression are affected, the PLLP is misrouted and migrates onto the yolk sac. (C) The whole mount flh embryo was stained to reveal expression of cxcr4b (dorsal view); the two PLLPs are indicated by white arrows. White dashed lines demarcate the plane of sections in D and E, PLLPs are indicated by black arrows. (F,G) The lateral line axon is detected by anti-acetylated-α-tubulin antibody in 48hpf embryos (black arrowhead). The mutant axon is misrouted similar to the PLLP in B. Abbreviations: nt – neural tube; ov – otic vesicle; ys – yolk sac; yse – yolk sac extension.

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Migration of Neural Cells Regulated by SDF-1α - CXCR4 During CNS development in vertebrates, neural progenitor cells migrate from the inner germinal layer where they are born to their final destinations close to the outer pial surface. In another region of the brain, during development of the dentate gyrus, a part of the hippocampus involved in formation of new memory and regulation of happiness, the source of SDF-1α is in an outer brain envelope. The meninx acts as a chemoattractant for cell progenitors migrating from the inner germinal region facing the lateral ventricle. In this case, lack of SDF-1α synthesis results in block of migration of progenitors and lack of a properly developed dentate gyrus. In an analogous situation, SDF-1α acts as a chemoattractant for sensory neuron progenitors in the mouse that migrate from the neural tube to form the dorsal root ganglia (Belmadani et al., 2005). Here, insufficient Cxcr4 signaling results in malformed ganglia, similar to those seen in the Cxcr4b-deficient ody zebrafish mutant. Conversely, ectopic sources of the chemokine SDF-1α can attract sensory neurons (Knaut et al., 2005; Miller and Tran, 2005). SDF-1α regulates β-catenin transcriptional activity in rat neural progenitors. It promotes nuclear TCF/LEF DNA-binding activity and enhances β-catenin nuclear translocation. SDF1α stimulation increases expression of target genes by activation of β-catenin/TCF/LEF transcription complexes. These include Ccnd1-3 (cyclins D1-3) for cell division and the transcription factor c-Myc (Luo et al., 2006). Recently, it was shown that the activation of cAMP-dependent protein kinase can phosphorylate ser675 of β-catenin, resulting in the inhibition of ubiquitination of β-catenin, thus stabilizing β-catenin and enhancing its transcriptional activity (Hino et al., 2005). β-catenin/TCF/Lef are well-established signal transducers of the canonical Wnt pathway. These recent data identified therefore a convergence of chemokine signaling and canonical Wnt signaling with β-catenin as the point of convergence.

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Cell Determination/Differentiation Requires Cxcr4-Sdf1 Signaling Previous studies indicated that Cxcr4 is expressed in somites of vertebrate embryos (Chong et al., 2001; McGrath et al., 1999). In a subsequent report, muscle satellite cells of adult humans, which are pivotal for regeneration of muscles, were found to express high levels of CXCR4 at the cell surface (Pituch-Noworolska et al., 2003). However, the role Cxcr4 in the development of trunk muscle was not addressed until recently. The zebrafish chemokine receptors cxcr4a and cxcr4b are expressed in most cells of nascent somites. During development, the expression domains of these genes in more mature somites become restricted to the anterior portion of each somite (Chong et al., 2001; Chong et al., 2007). In contrast, both ligands sdf1a and sdf1b are expressed strongly only in the posterior part of the somites. The anterior somitic cells, which express early markers such as pax3 and pax7, are less differentiated compared to posterior somitic cells, which express markers such as myf5 and myoD. And these anterior somitic cells express cxcr4 at a higher level (Figure 2), suggesting that Cxcr4 could act upstream of myogenic regulatory factors (MRF) such as MyoD. Importantly, Sdf1a-Cxcr4a signaling has been shown to have an

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essential role in primary myogenesis and in particular, in the regulation of MyoD expression (Chong et al., 2007). The function of Sdf1a -Cxcr4 in myocytes during myogenesis is further supported by results of the knockdown of Pbx or MyoD, which blocked cell differentiation and resulted in a prolonged maintenance of cxcr4a expression (Maves et al., 2007). This correlates with the up-regulation of another myogenic factor myf5 or increase in expression of Pax3/7, a pair of early developmental regulators required to maintain a pool of undifferentiated myoblasts (Hammond et al., 2007; Lin et al., 2006). Interestingly, the reduction of Sdf1a - Cxcr4 causes down-regulation of MRFs and yet also reduces Pax7. Perhaps, Sdf1a - Cxcr4 signaling pathway could be an important factor for myoblast “stemness” without which cells will be stalled in stasis. Taken together, these data support the observation that Sdf1a - Cxcr4 signaling is involved in primary myogenesis (Chong et al., 2007). It has been shown previously that Sdf1α-Cxcr4 could regulate MRFs in other types of muscles (Vasyutina et al., 2005; Yusuf et al., 2006), but we demonstrated this link for the first time during development of trunk muscles. Our study also suggested that there is a regulatory feedback loop from MRFs back to Cxcr4 (Chong et al., 2007).

Figure 2. SDF-1-CXCR4 signaling during somitogenesis (dorsal view). As somites mature the expression of cxcr4 becomes restricted to the anterior (less differentiated) part of somite (yellow). Large arrows indicate Sdf-1 contributed by the posterior part of somites. Small arrows indicate that Sdf-1 may be contributed by small Sdf-1-positive cell clusters in the anterior somite. Abbreviations: A – anterior part of somite; n – notochord; P- posterior part of somite; S – somite; S1 - the newly formed somite; S0 - the forming somite.

It was shown before that MRFs and Sdf-1α function within a context of the Hedgehog (Hh) signaling. Hh is known to induce expression of myf5 and myoD and SDF-1α has the ability to induce the chemotatic and proliferative responses of precursors of cerebellar cells to

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Hh signaling (Borycki et al., 1999; Concordet et al., 1996; Gustafsson et al., 2002; Klein et al., 2001; Lewis et al., 1999; Schauerte et al., 1998). Whereas these studies demonstrated that Hh acts as a positive regulator of MRFs, our study showed that the same signaling represses transcription of cxcr4a (Chong et al., 2007). These results support previous observation that Shh-mediates down-regulation of CXCR4 on the surface of CD34+ intrathymic precursor cells (Gutierrez-Frias et al., 2004). Therefore developmental events involving Hh during early myogenesis are much more complex that it was thought earlier. Currently experiments are in progress aiming to identify molecules involved in the Sdf1-Cxcr4 pathway that act during differentiation of trunk muscles. For example, further analysis could be instrumental in understanding the role of Cxcr4b, Cxcr7 and Sdf-1b in development of slow muscle precursor cells (Chong et al., 2001; Chong et al., 2007 and our unpublished results). In conclusion, despite complexity of a biological function of the Sdf1a-Cxcr4 axis, an introduction of zebrafish as a novel model system for analysis of chemotaxis or developmental processes such as determination/differentiation provided research tools necessary to understand fine details of this process in vertebrates in vivo with single cell resolution.

ACKNOWLEDGEMENT We thank Kathleen Osborne and Hoon-Hoon Tan for helpful discussions and critical reading of this manuscript. VK laboratory is funded by the Agency for Science, Technology and Research (A*STAR) of Singapore.

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INDEX

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A abdomen, 258 abdominal, 196 abnormal, 192, 193 abnormalities, 258, 259 abortion, 160, 183, 199, 202, 204, 205, 206, 207 absorption, x, 241, 243, 244, 263, 266 abstinence, 157, 160, 180, 181, 215 abuse, 159, 160, 168, 170, 182, 183, 209, 225, 227, 230, 231 abusive, 199 access, 7, 26, 30, 32, 132, 134, 135, 137, 138, 139, 142, 163 accumulation, 258, 259 acetate, 246, 254, 263 achievement, 9, 31, 45, 275 acid, 242, 248, 249, 256, 259 acidosis, 256 Acquired Immune Deficiency Syndrome AIDS, i, iii, iv, v, vii, viii, ix, x, xi, 1, 3, 10, 13, 14, 15, 16, 17, 19, 20, 21, 22, 24, 27, 28, 29, 31, 32, 33, 35, 38, 39, 43, 47, 48, 55, 58, 59, 60, 61, 63, 64, 67, 72, 73, 76, 82, 83, 84, 86, 87, 88, 91, 92, 93, 97, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 113, 114, 115, 117, 118, 123, 126, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 142, 143, 145, 146, 147, 148, 149, 150, 151, 153, 155, 156, 157, 158, 160, 171, 176, 179, 182, 183, 185, 188, 192, 195, 212, 213, 214, 215, 216, 217, 219, 224, 225, 226, 227, 230, 231, 235, 236, 237, 238, 239, 241, 242, 245, 250, 251, 253, 255, 264, 266, 268, 269, 272, 278, 283, 293, 294

acquired immunity, viii, 117, 296 acquired immunodeficiency syndrome, vii, 19, 250, 266 acquisition of knowledge, 14 actin, 283 activation, x, 90, 97, 104, 108, 113, 121, 125, 126, 241, 243, 245, 249, 250, 251, 259, 260, 261, 267, 271, 275, 278, 279, 284, 289, 297, 303, 304, 305, 308, 310 activation state, 90 activators, 261 activities, 157, 163, 164, 165, 166, 178 acute, x, xi, 2, 20, 29, 32, 38, 40, 89, 90, 110, 112, 122, 137, 271, 272, 274, 275, 279, 281, 284, 285, 286, 287, 288, 289, 291, 292, 295, 296, 297, 299 acute infection, 29, 32, 90 acute rejection, 285, 286, 289, 299 Adams, 109, 128 addiction, 194 additives, 62 adenovirus, 118 adhesion, 120, 121, 126, 242, 243, 250, 265, 284 adipocyte, 259 adipocytes, 258, 259 adipose, 244 adipose tissue, 244 adjustment, 137, 150, 263 administration, 12, 23, 32, 33, 34, 38, 43, 51, 57, 71, 73, 74, 89, 103, 260 administrative, 157 adolescence, 154, 155, 164, 212 adolescent, 156, 157, 158, 181, 188, 198, 207, 212, 225, 233, 234, 236, 237, 238, 239

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314

Index

adolescents, 84, 157, 159, 166, 178, 180, 181, 185, 188, 198, 208, 215, 226, 235, 236, 237, 239 adult, 64, 132, 133, 141, 142, 157, 163, 197, 209, 210, 212, 217, 278, 292, 305 adult population, 64, 132, 133, 141 adulthood, 154, 165, 212, 238 adults, 13, 14, 64, 84, 129, 136, 138, 163, 186, 188, 197, 208, 209, 216, 217 advances, 185, 212 adverse event, 266 advertising, 140 affect, 158, 176, 214 Africa, v, ix, 11, 13, 14, 40, 64, 73, 88, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 157, 158, 162, 178, 179, 180, 181, 185, 198, 208, 212, 215, 225, 234, 235, 236, 237, 238, 239 African American, 79, 277 African Americans, 79, 277 African culture, 157 afternoon, vii, 1, 16, 59 age, 12, 15, 28, 79, 80, 81, 88, 156, 157, 161, 162, 177, 178, 179, 180, 182, 183, 184, 185, 186, 195, 196, 200, 202, 203, 205, 206, 208, 209, 210, 212, 213, 224, 227, 228, 234, 236, 283, 288, 291 agent, 3, 6, 7, 16, 17, 18, 24, 28, 30, 48, 55, 98, 260 agents, viii, 2, 29, 87, 135, 208, 255, 261, 263 aggregation, 249, 259, 267, 268, 269 aggressive behaviour, 157, 211 aging, 257 agonist, 310 agricultural, 140, 141, 144, 158 agriculture, 6, 134 aid, 73, 144, 147, 272 air, 42, 251 Albert Einstein, 45 alcohol, 169, 170, 185, 186, 200, 211, 213, 220, 221, 225, 226, 227, 229, 230, 231 alcohol use, 225, 226, 227, 230, 231 alien, 130 alkanes, 251 allele, xi, 105, 272, 273, 275, 277, 278, 280, 282, 283, 286, 287, 288, 289, 293, 294, 298 alleles, 41, 100, 277, 279, 285, 288 allo-antigen, 100, 272 allogeneic, v, x, xi, 41, 100, 271, 272, 273, 274, 275, 278, 281, 282, 283, 284, 286, 287, 288, 289, 290, 291, 292, 293, 295, 296, 298

allogeneic HSCT, xi, 272, 273, 275, 281, 282, 283, 284, 287, 288, 290, 295 allograft, x, 271, 284, 285, 286, 297, 299 allografts, 289 allotransplantation, 275 alpha, 123, 261, 264, 265, 267, 268, 301, 309 alpha-tocopherol, 261, 264, 265, 267 alternative, 28, 30, 37, 63, 66, 90, 91, 143, 156, 255, 288, 310 alternative hypothesis, 310 alternatives, x, 241 ambivalent, 208 amelioration, 279 amino, 103, 259, 276, 277, 303 amino acid, 103, 259, 276, 277, 303 amino acids, 103, 277 amorphous, 278 amphibians, 303 Amsterdam, 149 anaemia, 36 analog, 255 anatomy, 235 anemia, 243 anger, 154, 199 Angola, 133 animal models, viii, 18, 21, 32, 88 animal studies, 288 animals, 2, 5, 6, 7, 35, 62, 89, 93, 98, 99, 100 anion, 243, 256, 257, 269 anorexia, 243 anthrax, 6 anthropological, 155, 238 antibiotic, 50 antibiotics, 261 Antibodies, 20, 89, 98, 99, 103 antibody, 8, 9, 18, 20, 21, 23, 26, 30, 36, 37, 40, 41, 42, 43, 56, 57, 71, 79, 89, 91, 94, 96, 107, 112, 114, 218, 219, 304 anticoagulant, 34, 37 antigen, viii, 4, 12, 20, 36, 38, 78, 79, 80, 92, 95, 97, 98, 104, 106, 108, 109, 117, 118, 120, 121, 122, 123, 124, 126, 245, 250, 284, 289 antigen presenting cells, 250, 284, 289 antigen presenting cells (APCs), 284 antigen-presenting cell, 118, 122 Antigens, 295 anti-HIV, 13, 15, 18, 19, 20, 21, 26, 29, 30, 33, 36, 40, 41, 51, 56, 57, 71, 85, 110, 120, 122, 276 anti-inflammatory, 93 antimicrobial, 12

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Index antioxidant, x, 241, 243, 244, 245, 249, 250, 251, 253, 256, 257, 261, 263, 264, 265, 266, 267, 269 antioxidants, 243, 245, 256, 263, 266, 268 antiretroviral, 14, 23, 26, 43, 56, 89, 123, 127, 144, 245, 248, 253, 255, 256, 258, 259, 261, 263, 265, 266, 267, 268, 269 antiretrovirals, 43, 44, 46, 248, 263 antisera, 102 antiviral, viii, x, 43, 88, 96, 97, 107, 109, 127, 242, 246, 273, 274, 275, 290 antiviral therapy, 290 AP, x, 110, 241, 242, 245, 250, 254, 292, 294 apartheid, 158, 239 Apartheid, 158, 235 APCs, 118 aplasia, 244 apoptosis, x, 106, 241, 242, 244, 245, 248, 249, 250, 251, 253, 259, 263, 264, 265, 266 apoptotic, 250, 251 application, 32, 44, 106, 128, 160, 238 argument, 134 Arizona, 279, 280 aromatic hydrocarbons, 265 arsenic, 120, 125 arthritis, 40, 275 ascorbic, 249 ascorbic acid, 249 Asia, 139, 166 Asian, 155, 159, 277, 280, 281 Asian countries, 155 assault, 14, 210 assertiveness, 157 assessment, 4, 21 assets, 135, 142 assignment, 30, 31, 33, 34 association, 225, 227, 248 associations, 272, 273, 283, 288 assumptions, 131, 134 astrocytes, 276 asymptomatic, 20, 91, 92, 104, 212, 251, 253, 256, 278 Athens, 147 atherosclerosis, 255, 257, 258, 259 atrophy, 244 attachment, 28, 127 attention, vii, ix, 1, 13, 24, 41, 59, 67, 68, 130, 131, 132, 133, 134, 136, 156, 176, 237, 259 attitudes, 156, 160, 180, 188, 207, 208, 233, 235, 237, 238, 239 atypical, 36

315

Australia, 83, 91, 156 authenticity, 46 authority, 22, 32, 154, 157 autocrine, 245 autoimmune, 11, 250, 260 autoimmune disease, 11, 250 autoimmune diseases, 11, 250 autonomous, 234 Autonomous, 130, 310 autonomy, 133, 234 availability, 25, 26, 48, 65, 263 awareness, 156, 174, 238 axon, 304 axonal, 301 axons, 303, 308, 309

B B cell, 90, 94, 95, 106, 109, 250, 276, 278, 279, 281, 295 babies, 42, 203 bacilli, 7 Bacillus, 103 bacteria, 2, 5, 97, 245, 257 bacterial, 272 bacterial infection, 272 barrier, 94, 101, 110, 120, 126, 272 barriers, 89, 137 base pair, xi, 250, 254, 272, 276 basic rights, 137 Bax, 251 B-cell, 294 beating, 211 behavior, 156, 157, 180, 192, 211, 216, 217, 225, 227, 228, 232, 234, 238, 301, 303, 310 behaviour, ix, 82, 130, 153, 155, 157, 171, 158, 181, 193, 197, 199, 211, 213, 217, 235, 236, 237, 238, 239 belief systems, 132 beliefs, 238 beneficial effect, 243, 254, 263 benefits, 24, 25, 26, 139, 193, 195, 259, 263 beta, 111, 112, 265, 267, 273, 275, 283, 290, 293, 298, 308, 309 beta-carotene, 267 bicarbonate, 256 bilateral, 25, 143, 144 bilateral aid, 144 bilateral trade, 143

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Index

binding, 18, 20, 34, 94, 103, 106, 111, 114, 118, 123, 126, 242, 243, 245, 254, 258, 259, 261, 279, 301, 305 binge drinking, 221 bioavailability, 263, 269 biochemical, 56 biochemistry, 266 biodegradable, 95 biogenesis, 127 biological, 84, 158, 162, 189, 208, 264, 307 biology, 15 biomarker, 256 biomedical, ix, 130, 153 biopsies, 274 biopsy, 285 biosynthesis, 258 birth, 12, 42, 167, 168, 169, 196, 199, 200, 201, 202, 204, 205, 206, 207 black, 131, 134, 158, 196, 208, 225, 239, 304 Blacks, 158 blame, 42, 205 blastoderm, 302 bleeding, 197 blindness, 4 blocks, 97, 122, 138, 245, 254, 302, 307 blood, vii, 4, 8, 10, 12, 13, 14, 15, 17, 19, 20, 24, 29, 30, 32, 33, 34, 35, 36, 37, 38, 42, 43, 62, 71, 74, 76, 78, 79, 80, 86, 92, 114, 118, 119, 123, 124, 127, 196, 210, 253, 276, 278, 280, 281 blood group, 36, 37, 80 blood transfusion, vii, 33, 34, 36, 37, 38, 74, 79 blood transfusions, 33, 36, 74, 79 bloodstream, vii, 82 blot, 85 B-lymphocytes, 282 body, 156, 194, 195, 235 body fluid, 21, 100 body image, 235 bonds, 135 bone, 118, 276, 288, 289, 292, 293, 295, 310 bone marrow, 118, 276, 288, 289, 292, 293, 295, 310 bone marrow transplant, 288, 289, 292, 293, 295 Boston, 8, 235 Botswana, ix, 13, 129, 132, 133, 140, 141, 147, 149, 237 bowel, 275 boys, 136, 157, 159, 160, 161, 162, 163, 164, 165, 166, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 181, 182, 183, 185, 187, 188, 189, 190, 191, 192, 193, 195, 196, 197, 198, 199, 202, 203, 204,

207, 208, 209, 211, 213, 214, 215, 216, 217, 218, 220, 234, 235 brain, 245, 255, 266, 305 Brazil, 22, 83, 91, 143, 241 Brazilian, 268 breaches, 89 breakdown, 154, 211 breast, vii, 12, 29, 42, 210 breast feeding, 29 breast milk, vii, 12 breastfeeding, vii, 26 Britain, 80 British, 47, 48, 52, 54, 56, 64, 65, 66, 146, 236, 239, 286 broad spectrum, 122 brothers, 192, 199, 222 bubble, 9 budding, 20, 121 Burundi, 133 Bush Administration, 144 business, 13, 223 bypass, 119 bystander cells, 250

C Caenorhabditis elegans, 266 calcium, 268, 303, 309, 310 California, 9, 148, 279 Cameroon, 133, 188 campaigns, 28, 131 Canada, 76, 83, 91, 138, 144 Canberra, 145, 236 cancer, 11, 250 Cancer, vii, 1, 16, 265, 266, 295 cancerous cells, 11 cancers, 20, 39 candidates, viii, 87, 90, 91, 99 candidiasis, x, 241, 243 cannabis, 220, 221, 225, 227, 229, 230, 231 capacity, 2, 25, 64, 132, 142, 185, 250, 253, 254, 259, 261, 262, 263 Cape Town, 159, 180, 188, 208, 236, 237, 238, 239 capital, 132, 139, 140, 141, 142, 143, 144 capital flows, 140, 143 capitalism, 139 capitalist, 133 carboxyl, 301 carcinogenesis, 265 cardiovascular, 257

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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Index cardiovascular disease, 257 caregivers, 208 Caribbean, 150 carotene, 249, 256, 257, 267 carotenoids, 266 carrier, 75, 91, 103, 212, 280 caspase, 251 caspases, 250 cast, 143 catabolism, 40, 268 catalase, 242, 251 catalyst, 155 catalytic, 259 Catholic, 202, 223 cats, 8 cattle, 142 Caucasian, 279, 280, 281, 294 Caucasian population, 294 Caucasians, 98 causation, 133, 136 CB, 105, 293 C-C, 114, 273, 275, 293 CCR, 286, 294, 297, 298, 299 CD, 242 CD14, 91, 102, 119, 289 CD19, 119 CD20, 119, 278, 284, 294 CD28, 95, 125 CD3, xi, 119, 125, 272, 277 CD34, 118, 119, 124, 307, 308 CD34+, 118, 119, 307, 308 CD4, v, viii, x, xi, 19, 20, 21, 29, 37, 41, 43, 44, 56, 84, 87, 88, 89, 90, 91, 92, 93, 94, 96, 97, 98, 99, 100, 102, 103, 104, 107, 108, 110, 111, 113, 114, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 241, 248, 250, 251, 253, 254, 256, 257, 268, 272, 275, 278, 281, 289, 293, 295, 297, 301 CD40, 95, 99, 111, 114, 119, 120, 121, 124 CD8+, 11, 21, 84, 85, 89, 91, 93, 96, 97, 102, 103, 104, 105, 110, 114, 122, 128, 248, 268, 289 CD95, 106, 251, 267 CDC, 38 cDNA, 95 CE, 85 cell, viii, x, xi, 2, 11, 12, 19, 20, 21, 29, 33, 34, 40, 41, 42, 44, 82, 84, 85, 87, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 105, 107, 110, 111, 113, 115, 118, 120, 121, 122, 123, 126, 127, 241, 243, 244, 245, 246, 248, 250, 251, 253, 254, 256, 257, 258, 264, 266, 267, 268, 271, 272, 277, 278, 284, 287,

317

289, 290, 291, 292, 294, 297, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310 cell adhesion, 243 cell culture, 2, 245, 246, 248, 254 cell death, 96, 245, 250, 266, 268 cell differentiation, 306 cell division, 302, 305 cell fate, xi, 300 cell line, xi, 300, 302 cell membranes, 12, 256 cell signaling, 244 cell surface, xi, 91, 92, 98, 111, 121, 254, 272, 277, 294, 297, 305 cell transplantation, 290 cellular immunity, 12, 106, 278 cement, 13 Centers for Disease Control, 84 Central Europe, 277 central nervous system, 276, 302 cereals, 141 cerebellar development, 311 cerebellar granule cells, 309 cerebellum, 301 certificate, 222 cervical, 258 cervix, 111 Chad, 133 channels, 25 chaos, 205 character, 168 cheating, 134, 168, 169, 170, 175, 192, 211 chemical, 34, 62, 301 chemicals, 34, 265 chemistry, 6, 282 chemoattractant, 301, 305, 307 chemokine, x, xi, 91, 95, 97, 98, 102, 103, 105, 109, 110, 111, 112, 114, 115, 254, 271, 272, 273, 275, 277, 285, 289, 293, 294, 296, 297, 298, 299, 300, 301, 303, 305, 307, 308, 309, 310, 311 chemokine receptor, x, xi, 91, 102, 109, 110, 111, 112, 114, 115, 271, 273, 275, 277, 285, 289, 293, 294, 296, 297, 298, 299, 300, 301, 305, 308, 309, 310, 311 chemokines, x, 42, 85, 95, 96, 97, 98, 100, 102, 106, 108, 109, 114, 254, 267, 271, 275, 278, 281, 284, 285, 295, 310 chemotaxis, 114, 300, 301, 303, 307, 308, 309 chemotherapeutic agent, 36 chemotherapy, 88 Chemotherapy, 267

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318

Index

chest radiograph, 36 Chicago, 147, 150 Chief Justice, 56 Chief of Staff, 68 child abuse, 160 child rearing, 135 childbearing, 135, 208, 238 childbirth, vii childhood, 2, 154, 157, 165, 197 children, 7, 8, 9, 10, 13, 42, 50, 52, 132, 135, 138, 142, 150, 154, 158, 162, 167, 194, 203, 207, 209, 211, 232, 233, 235, 236, 237, 273, 292, 294 Chimpanzees, 93 China, 138 Chinese, 5, 144 cholera, 2, 6, 7, 12, 94 Cholera, 96 cholesterol, 257 Christmas, 169, 223 chromatin, 250 chromosome, 79, 276 chromosomes, 253 chronic, x, 19, 40, 88, 93, 103, 106, 113, 122, 241, 245, 256, 257, 267, 274, 279, 280, 285, 287, 288, 291, 292, 296, 297, 298, 299 chronic viral infections, 93, 103 cigarettes, 221 circulation, 94, 106 circumcision, 13, 132 cis, 120, 121, 124, 259 citizens, 14 Civil War, 146 civilian, 57 classes, 53, 114, 135 classification, 38, 84, 288 classified, 221, 286 cleaning, 165 cleavage, 250 clinical, xi, 7, 25, 26, 28, 31, 40, 44, 51, 55, 70, 80, 81, 82, 84, 89, 248, 257, 261, 265, 272, 289, 290, 293, 294, 295, 298 clinical symptoms, xi, 272 clinical trial, 25, 26, 51, 70, 89, 248, 261 clinical trials, 25, 26, 51, 70, 89, 248, 261 clinician, 32 clinicians, 20, 36, 257 clinics, 137, 201, 215 clones, 112 cluster, 159 cluster of differentiation, 19

clusters, 277, 303, 306 c-Myc, 305 coal, 139 coalitions, ix, 130 Coca-Cola, 45 codes, 92, 132 coding, 278 coenzyme, 256 coercion, 156, 159 cofactors, 256 coffee, 211 cognitive, 140 cognitive dissonance, 140 cohesion, 211 cohort, 180, 266, 280, 298, 303 coitus, 29, 178, 187, 200 Coke, 45 collaboration, 24, 64, 65, 151 colonial, 130, 133, 134, 135, 137 colonialism, 133, 134, 136, 140 colony-stimulating factor, 123 Colorado, 279, 280 colostrum, 12 combat, 142 combined effect, 136 commercial, 24, 107, 135, 139, 158, 159 commitment, x, 171, 188, 241 commodities, 139, 140 commodity, 139 commodity producers, 139 communication, 30, 154, 156, 166, 167, 226 communities, 23, 24, 25, 26, 64, 138, 142, 154, 208, 211, 225 community, 23, 26, 94, 144, 154, 156, 192, 205, 206, 211, 217 compatibility, 33 compensation, 160 competence, 39, 154 competition, 143, 154 complement, 23, 97, 290 complementary, 90, 109 complex, 156 complexity, 133, 307 compliance, 15 complications, ix, 129, 272, 273, 274, 283, 290, 291 components, xi, 15, 32, 34, 103, 120, 160, 235, 300, 303 composition, 127, 245 compounds, 261 comprehension, 45, 66

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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Index computer, 223 computers, 3 concentrates, 33 concentration, 62, 100, 130, 246, 254, 256, 257, 263, 301 concept, 157 conception, 27, 157 concordance, 38, 41, 85 concrete, 64, 65 concurrency, 134, 135, 144 condensation, 250 conditioning, 278, 283, 288, 289, 291, 295, 296 condom, x, 134, 153, 159, 169, 173, 187, 198, 200, 204, 205, 210, 213, 214, 215, 217, 218, 219, 224, 225, 226, 227, 230, 231, 235, 237, 238 condoms, 13, 26, 82, 137, 141, 156, 157, 158, 181, 182, 188, 205, 206, 208, 212, 213, 215, 217, 219, 225, 235, 237 conduct, 155, 159, 160 confidence, 37, 75, 192 configuration, 245 conflict, 26, 137 conflict of interest, 26 conflicts, 170 conformity, 144, 234 confrontation, 154 confusion, 59 Congress, iv, 72 conjugation, 261 conscientiousness, 4 consensus, 21, 23, 93 consent, 8, 9, 36, 160 consequence, 154 conspiracy, 75 constitution, 156 constraints, 194 construction, 130, 155, 207, 235, 237 consumerism, 140 consumers, 140 consumption, 141, 155 content, 235 content analysis, 235 context, ix, x, 153, 154, 156, 158, 160, 166, 167, 211, 212, 236, 237, 238, 242, 244, 257, 263 contexts, 155 continuing, 93 continuity, 154 contraceptives, 155, 181, 187, 198, 200, 204, 205, 206 contractors, 144

319

control, viii, 2, 3, 6, 10, 21, 24, 26, 40, 68, 78, 79, 80, 81, 84, 85, 87, 89, 90, 91, 93, 97, 104, 105, 107, 110, 114, 118, 122, 123, 127, 154, 156, 157, 158, 180, 185, 190, 232, 234, 239, 248, 251, 253, 261, 266, 272, 274, 279, 301, 302, 304, 310 control group, 2, 91, 251, 253, 261 controlled, 141, 190, 213, 248, 249, 253, 256 controlled trials, 256 convergence, 305 conversion, 39 cooking, 165 cooperation, 174 coordination, 64, 65, 132 copper, 244 copyright, iv correlation, 89, 133, 137, 285, 286, 287, 292 correlations, 78, 208, 219, 273, 288 corruption, 46 cortical, 310 costimulatory molecules, 121 costs, 25, 140, 142, 143, 248, 263 cotton, 8 coughing, 212 couples, 90, 163 courts, 68 coverage, 46 craniofacial, 309 C-reactive protein, 243, 292 credit, 17 crime, 11, 142 crimes, 6 criticism, 7, 34 cross-cultural, 235, 238 cross-cultural psychology, 235 cross-linking, 289 crying, 170 Cryptococcus, 255 C-terminal, 259 cultural, ix, 131, 132, 134, 136, 153, 156, 235, 238 cultural practices, 131, 134 culture, ix, 10, 14, 62, 92, 103, 131, 153, 192, 211, 235, 238, 248, 273 cultures, 156, 157, 238 cumulative, 178 curable, 30 currency, 136, 142 cycles, 136, 263 cyclic AMP, 308 cyclins, 305 cyclooxygenase, 250, 259

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index

320

cysteine, 245, 249 cytochrome, x, 242, 251, 259, 261 cytokine, x, 95, 96, 102, 114, 245, 249, 250, 257, 271, 272, 273, 274, 284, 292, 296 cytokines, 12, 42, 85, 93, 94, 95, 96, 97, 114, 244, 245, 249, 258, 278, 284 cytomegalovirus, 273, 274, 278, 295, 298 cytometry, 276 cytoplasm, 19, 20, 29, 251 cytoplasmic tail, 303 cytosolic, 257 cytotoxic, viii, 11, 21, 41, 42, 43, 84, 85, 87, 88, 89, 91, 94, 96, 97, 100, 103, 104, 105, 112, 122, 278, 281 Cytotoxic, 89

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D dairy, 5 Dallas, 310 damage, 194, 244, 245, 249, 251, 253, 256, 264, 265 danger, 12, 77, 95, 195, 216, 217 database, 79 dating, 137 daughter cells, 20 death, ix, 3, 6, 8, 13, 14, 16, 19, 21, 23, 24, 29, 31, 33, 64, 129, 130, 138, 139, 142, 210, 245, 250, 266, 268 death rate, 3, 13 deaths, ix, 3, 8, 10, 13, 14, 76, 129 debt, 144 decision making, 156 decisions, 25, 135 decoding, 80 defects, 244, 294 defense, 123, 244, 253, 256, 269, 273 defenses, 251 deficiency, vii, 29, 138, 244, 251, 298 definition, 23, 30, 84, 97, 134, 139, 282 degradation, 120, 259, 263, 301 degree, 25, 52, 154, 185, 212, 222, 233, 272 delays, 278 delivery, 42, 66, 94, 108, 111, 122 delta, 265 Delta, 105, 298 demand, 15, 144, 168, 169, 218, 234 democracy, 68 Democratic Republic of Congo, 133, 137 demographic, 180, 236, 238

dendritic cell, v, 19, 91, 95, 97, 99, 106, 107, 111, 112, 114, 117, 123, 124, 125, 126, 127, 289, 297 Dendritic cells, viii, 104, 117, 118, 123, 126 density, 242, 255, 259, 265, 267, 268 dentate gyrus, 305 deoxyribonucleic acid, 242 dependent, 208 dephosphorylation, 260 deposition, 40 deposits, 303, 304 depreciation, 140 depressed, 197 deprivation, 244 derivatives, 302 desensitization, 102 desiccation, 29 desire, 71, 132, 135, 140, 154, 158, 185, 186, 188, 189, 190, 191, 193, 194, 196, 197, 234, 239 desires, 189, 190, 191, 195 destruction, 12, 40, 41, 43, 88, 90, 92, 120, 250, 260 detection, 19, 21, 33, 273, 275, 282 detoxification, 261 devaluation, 136 developed countries, 12, 14, 15, 23, 24, 29, 45, 47, 69, 71, 88, 156 developed nations, 46 developing countries, viii, x, 21, 23, 24, 44, 64, 65, 87, 153, 155, 156, 239 development, 211, 212 Development, 236 developmental process, 302, 307 diagnostic, 20 diarrhea, x, 241, 243 diarrhoea, 36 Diaspora, 67 diet, x, 140, 241, 243, 244, 249 dietary, 244 differences, 155, 161, 164, 189, 191, 207, 216, 223, 224, 225 differential rates, 135 differentiation, x, 120, 125, 250, 271, 278, 284, 289, 297, 302, 305, 307, 308, 309 digestive tract, x, 241, 243 dignity, 27, 28, 192 diphtheria, 2, 12 disability, 207 discounting, 140 discourse, ix, 153, 232 discrimination, 19, 26 disease, 155, 182, 195, 207, 212, 216, 217

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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Index disease progression, x, 19, 23, 96, 105, 108, 127, 241, 244, 248, 250, 253, 255, 264, 265, 266, 267, 278, 294 diseases, 5, 12, 14, 31, 131, 138, 195, 257 disorder, 140, 260, 273, 278, 292, 294 disposable income, 142 disposition, 262 dissatisfaction, 173, 182 distal, 303 distress, 206 distribution, 25, 40, 56, 79, 80, 91, 106, 136, 159, 294 diversity, 43 dividends, 3, 68 doctor, 5, 6, 17, 62, 64, 65, 67, 68, 202, 223 doctors, 6, 7, 9, 13, 27, 51, 64, 71, 136, 200, 201 dogmas, vii, 1 dogs, 7, 8 domestic violence, 141 dominance, ix, 40, 153 Dominican Republic, 83, 91 donations, 9 donor, 25, 32, 38, 80, 81, 86, 119, 143, 272, 273, 274, 277, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 296, 297, 299 doors, 8 dosage, 35, 37, 267, 294 down-regulation, 258, 306, 307 dream, 14, 71 drinking, 140, 165, 170, 174, 175, 221 drug, 216 drug interaction, x, 241, 263, 269 drug therapy, 3, 267 drug use, 112, 216 drug-induced, 258 drugs, 3, 13, 14, 29, 32, 43, 56, 88, 139, 143, 148, 175, 185, 186, 211, 213, 216, 221, 262 drugs [medicines], 175, 185, 186, 211, 213, 216, 221 drugs [narcotics], 175, 185, 186, 211, 213, 216, 221 dry, 135, 157, 212 drying, 135 duplication, 302 dynamin, 301 dysfunctional, 96 dysregulation, x, 271, 284, 295

E E.coli, 95 early warning, ix, 129

321

earth, 4, 5 earthquake, 13 East Asia, 166, 277 eating, 140, 212 EBV infection, xi, 272, 278, 281, 282, 295 economic, vii, viii, ix, 1, 44, 46, 64, 72, 87, 88, 131, 133, 134, 135, 137, 138, 140, 141, 142, 143, 144, 148, 151, 153, 158, 159, 211 economic change, 151 economic crisis, 137 economic development, 64 economic globalisation, 137 economic growth, 140, 142, 144 economic liberalization, 133, 141 economic problem, 144 economic status, 159, 211 economics, 3 economies, 132, 134, 135, 137, 144 economy, x, 131, 133, 134, 135, 136, 137, 139, 140, 141, 143, 153, 238 ED, 148 edema, 243 education, 26, 137, 142, 143, 158, 159, 161, 206, 209, 213, 221, 222, 223, 224, 225, 226, 227, 230, 231, 233, 234, 235, 238 Education, vii, 1, 9, 16, 223, 225, 227, 235, 237, 238, 290 efficacy, 6, 7, 9, 10, 11, 23, 25, 26, 31, 32, 33, 35, 36, 40, 43, 71, 86, 256 ego, 215 Egyptian, 2 electricity, 38 electron, 251, 255, 278 electron microscopy, 255, 278 electronic, iv, 47, 67, 77 electrons, 251 electrostatic, iv elementary (primary) school, 159 email, 42, 70, 77, 79, 81 embryo, 301, 304, 309 embryonic, 302 embryos, 2, 304, 305, 311 emotion, 45, 174, 197 emotional, 190 emotions, 154, 190, 197 empirical research, 156 employees, 158 employment, 141, 142, 158, 182 empowerment, 131, 144

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322

Index

encoding, xi, 272, 273, 276, 277, 284, 285, 289, 290, 298, 300 encouragement, 47, 63 endocytosis, 301, 310 endogenous, 2, 12 endothelial cell, 250 endothelial cells, 250 endothelium, 265, 276 energy, 15, 258, 298 energy transfer, 298 engagement, 96, 138 engineering, 16, 17, 18, 24, 29, 30, 32 England, 5, 53, 79, 136, 265, 269 English, 5, 6, 30, 84, 160 engraftment, 289 Enhancement, 112 enlargement, 278 enterprise, 13 enthusiasm, 32, 51 envelope, 16, 17, 18, 19, 40, 85, 86, 92, 105, 109, 111, 113, 119, 278, 305 environment, 92, 93, 135, 137, 138, 275 environmental, 245, 261 environmental chemicals, 261 environmental conditions, 245 enzyme, 29, 251, 256, 257, 263 enzymes, 19, 20, 251, 253, 259, 261, 263, 265 epidemic, ix, 3, 7, 13, 15, 18, 24, 64, 72, 73, 83, 115, 131, 132, 133, 135, 143, 150, 153, 182, 212, 236, 239 epidemics, 2, 3 epidemiological, 41, 100, 136, 155 epidemiology, 131, 150, 265, 297 epidermal, 118 epistemological, 131 epithelia, 91, 96, 102, 107, 113, 119 epithelial cell, 92, 94, 100, 104, 112, 245 epithelium, 90, 92, 101, 276 epitope, 98, 109, 112, 114 Epstein-Barr virus, 273, 274, 292, 295 equilibrium, 154 equipment, 21, 26 equity, 26 erythema nodosum, 40, 275 erythrocytes, 244, 256 Escherichia coli, 105, 114 estates, 140, 144 esterases, 263 esters, 310 ethane, 251

ethical, 6, 10, 13, 21, 22, 23, 24, 25, 26, 27, 31, 64, 70 ethical concerns, 22 ethicists, 9, 21, 22 ethics, 17, 71, 160 Ethiopia, 138, 148, 178, 185, 236 Ethiopian, 236 ethnicity, 79 ethylene, 2 eukaryotes, 308 euphoria, 18 Eurasia, 277 Europe, 7, 166, 277, 294, 309 European, ix, 129, 150, 264, 267, 268, 269, 277 European Commission, 150 European Union, ix, 129 evening, 162 evidence, 4, 35, 36, 37, 40, 51, 64, 65, 71, 86, 91, 93, 97, 110, 121, 140, 146, 212, 235, 253, 278, 294, 295, 302 evolution, 85, 91, 108, 112, 284 examinations, 35 exclusion, 92, 131 excuse, 16 exercise, 34, 36, 48, 71, 140, 164, 182 exogenous, 107 exons, 294 exotoxins, 12 expectation, 157 expectations, 188 expert, iv, 61, 75 expertise, 21, 24, 42 experts, vii, 1, 15, 44, 73, 75, 82 exploitation, 123, 139 exposure, vii, 2, 12, 26, 67, 79, 89, 100, 112, 121, 135, 141, 195, 211, 248, 263, 278 expression, 248, 250, 251, 255, 258, 261, 266, 268 external locus of control, 154 extracellular, 12, 98, 110, 121, 301 extrinsic, 304 eyes, 205

F face validity, 160 factors, 156, 174, 233, 239 failure, vii, ix, 1, 3, 18, 21, 23, 34, 46, 47, 63, 82, 91, 103, 118, 123, 130, 266 false, 26, 77 false positive, 26

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Index familial, 232, 272 families, 154, 162 family, viii, 1, 28, 36, 47, 57, 69, 71, 76, 106, 123, 137, 142, 154, 158, 160, 165, 169, 190, 192, 199, 200, 203, 205, 206, 209, 210, 211, 216, 223, 235, 258, 261, 273, 275 Family, 162, 179, 211, 237 family members, 106, 142, 154, 165, 192, 210 family planning, 200, 235 family support, 142 famine, 3 farmers, 5, 6 farming, 5, 142 farms, 158 Fas, 106, 251, 267 FasL, 250 fat, 174, 244, 258 fatalism, 139 fatalities, 140 fatty acid, 251 fear, 8, 14, 34, 39, 157, 182, 183, 185, 193, 194, 200, 201, 202, 204, 206 fears, 182, 183, 193 February, 9, 55, 67, 69 feedback, 62, 306 feed-back, 274 feeding, 42 feelings, 154, 156, 183, 184, 189, 194 fees, 136, 137 female, 156, 157, 159, 161, 163, 178, 183, 185, 186, 190, 194, 198, 209, 213, 215, 216, 221, 222, 236 females, 155, 160, 163, 165, 178, 179, 180, 188, 189, 208, 212, 213, 215, 221, 224, 230, 231, 234 feminine, 211 feminist, 131 ferritin, 243 fertility, 198, 204, 238 fertilization, 204 fetus, 26 fever, 219, 243, 275 fibroblasts, 245, 257, 276 fibrosis, 280 field trials, 9 films, 185 financial problems, 38 financial support, 29, 158, 205 financing, 9, 10 firm, 157 fish, 139, 303 floating, 304

323

flow, 276 fludarabine, 295 fluid, vii, 92, 98, 108 fluorescence, 298 focus group, 163 focusing, xi, 250, 300 folate, 244 folic acid, 248 food, 136, 138, 269 Food and Drug Administration, 22 Food and Drug Administration (FDA), 22 football, 140 foreign aid, 143 foreign direct investment, 142 forgetting, 48, 50 formaldehyde, 2, 29 fowl, 6, 7 Foxp3, 93 fragility, 250 France, 15, 17, 69, 144 free, 166, 167, 188, 195 free choice, 131 free radical, 253, 255, 258 free radicals, 253, 258 freedom, 14, 164, 166, 167, 172, 182, 208, 213, 226, 228, 231, 233 freeze-dried, 2 freezing, 29 frequency, 163, 177, 181, 186, 209, 220 Frequency, 180, 181 friction, 135 Friday, 83, 200 friends, 164, 165, 170, 175, 182, 185, 186, 195, 200, 201, 203, 204, 206, 208, 209, 210, 211, 217 friendship, 192 frog, 8, 10, 14, 15 fulminant hepatitis, 256 functioning, 235 funding, 9, 15, 17, 30, 78, 144 funds, 8, 10, 21, 32, 42, 54, 71, 78 fungi, 245 fusion, 19, 119, 125, 275, 278

G G protein, 309 Gabon, 133 gamma globulin, 12 gamma radiation, 2 gamma-tocopherol, 268

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324

Index

ganglia, 305, 309 ganglion, 303 gangliosides, 94, 95 gases, 251 gastric, 92 gastrointestinal, 125, 243, 244, 262, 310 gastrointestinal tract, 125, 262, 310 gastrulation, 301, 302 gel, 187 gender, ix, 129, 133, 134, 135, 136, 143, 155, 157, 164, 165, 212, 221, 225, 234, 236, 237, 283, 288 gender differences, 165, 212 gender inequality, ix, 129, 135 gender role, 157 gender roles, 157 gene, v, xi, 12, 92, 113, 128, 244, 250, 254, 256, 257, 258, 261, 266, 267, 269, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 283, 284, 285, 286, 287, 290, 291, 292, 294, 295, 296, 297, 298, 299, 300, 302 gene expression, v, 244, 271, 272, 279, 281, 283, 296 gene therapy, 128 general surgeon, 28 generalizations, 12 generation, 2, 17, 19, 97, 103, 115, 249, 250, 251, 257, 275, 279 generations, 154 generators, 38 generic drug, 144 generic drugs, 144 generics, 144 genes, xi, 3, 20, 43, 89, 91, 245, 251, 258, 261, 272, 273, 281, 285, 290, 298, 300, 302, 305, 308 genetic, 16, 17, 18, 24, 29, 30, 32, 39, 84, 122, 140, 274, 277, 285, 297, 298, 299, 302 genetic screening, 84 Geneva, 22, 28, 50, 54, 70, 114, 149, 150, 239 genital herpes, 106 genocide, 143 genome, 19, 20, 29 genomes, xi, 43, 300 genomics, 290, 299 genotype, 272, 273, 275, 277, 278, 280, 282, 283, 284, 286, 287, 288, 290, 291, 292, 294 genotypes, 273, 277, 288 geography, 132, 140, 146 germ cells, 100, 301, 302, 303 germ layer, 301 Germany, 280

gift, 168, 169, 202, 205 gifts, 159, 168, 169, 177, 178, 213 Gini coefficients, 141 Ginkgo biloba, 256 girls, 135, 136, 157, 159, 160, 161, 162, 163, 164, 165, 166, 167, 170, 171, 172, 173, 174, 175, 176, 177, 178, 180, 181, 182, 183, 185, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 211, 213, 214, 215, 216, 217, 218, 219, 220, 225, 234, 235 GL, 84 gland, 268 global economy, 2, 131, 132, 139 global networks, 132 globalization, ix, 130, 131, 132, 133, 136, 137, 142, 143, 144, 145, 151 Globalization, v, ix, 129, 130, 133, 136, 139, 145, 149 globulin, 12, 278, 295 glomerulonephritis, 40 glutathione, 245, 251 glycoprotein, 105, 111, 115, 278 glycoproteins, 20, 245 glycosylation, 276 GM-CSF, 118 goals, 14, 21, 23, 26 God, 57, 194, 202, 205 going to school, 169 gold, 158, 236 gonad, 303 gonads, 301 goods and services, 142 government, iv, 22, 23, 25, 64, 65, 73, 74, 158 G-protein, 301 grades, 287, 288 graft-versus-host disease, x, 271, 272, 273, 274, 287, 291, 292, 293, 296, 297 graft-versus-host disease (GVHD), 296 graft-vs-host disease, 292, 296 Gram-negative, 97 grants, 64, 144, 290 granulocyte, 33, 123 graph, 78 grazing, 131 Great Britain, 15, 69 greed, 46, 75 groups, 25, 92, 118, 132, 140, 154, 221, 261, 303 growth, 11, 141, 142, 250, 273, 303, 309 guardian, 148, 157, 160

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index guidance, 21, 22, 23, 30, 57, 67, 304, 309 guidelines, vii, 1, 15, 22 guilt, 154 guilt feelings, 154 guilty, 11, 210 Guinea, 133 gut, viii, 87, 92, 93, 112, 284, 285 gyrus, 305

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H hair loss, 43 Haiti, 83, 91 half-life, 21 hands, 28, 29 hanging, 154, 156 haploid, 20 haplotype, 93, 286 haplotypes, 286, 294 happiness, 305 harassment, 160, 209, 210 harbour, 44 harm, 9, 25, 193 harmful, 193, 194, 255, 259 Harvard, 64, 148 harvest, 34 hate, 192, 237 head, 12, 18, 46, 64, 82, 83, 141, 142, 304 headache, 197 healing, 30 health, ix, 8, 21, 22, 24, 25, 26, 27, 30, 33, 36, 44, 69, 70, 76, 130, 136, 137, 138, 141, 148, 235, 236, 237, 238, 239 health care, 136, 137, 235, 239 health care professionals, 136 health education, 238 health services, 137 hearing, 4, 58, 66, 71, 78 hearing loss, 4 heart, 43, 256, 269, 285, 286, 299, 301 heart failure, 43 heart transplantation, 285, 286, 299 heat, 29, 95, 96, 97, 102, 103, 104, 105, 106, 111, 114, 273 heat shock protein, 97, 102, 103, 104, 111, 114 heating, 2 heavy, 196 helper cells, 93, 94, 249, 293 hematological, 260

325

hematopoietic, v, x, 124, 271, 272, 284, 286, 290, 291, 292, 294 hematopoietic progenitor cells, 124 hematopoietic stem cell, v, x, 271, 272, 284, 286, 290, 291, 294 hematopoietic stem-cell transplant, 291 hemophilia, 298 hepatic failure, 266 hepatitis, 2, 12, 13, 14, 16, 18, 36, 40, 256, 273, 278, 280, 281, 297, 298 hepatitis a, 256 hepatitis B, 12, 13, 16, 18, 36, 40, 273, 280, 297, 298 Hepatitis B, 4, 43, 279 hepatitis C, 14, 36, 278, 280, 281, 297, 298 Hepatitis C virus, 4, 43 hepatocytes, 245, 259 herbal, 43 herpes, 113, 273, 275 herpes simplex, 113 herpes virus, 273, 275 herpesviruses, 278, 292, 295 heterogeneity, 294 heterogeneous, 118, 245 heterozygosity, 280 heterozygotes, xi, 254, 272, 277, 280, 294 high risk, 20, 24, 26, 82, 90, 91, 158, 208, 211, 284 high school, 159, 215, 235, 237 higher education, 221, 222, 226, 230, 231 high-level, 113 Highly active antiretroviral therapy, 242 high-risk, 12, 16, 18, 118, 158 hip, 156 hippocampus, 305 histological, 280 history, 220 HIV, i, iii, iv, v, vii, viii, ix, x, xi, 1, 2, 3, 4, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 155, 156, 157, 158, 160, 171, 176, 179, 195, 208, 212, 213, 214, 215, 216, 217, 218, 219, 224, 225, 226, 227, 228, 230, 231,

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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Index

235, 236, 237, 238, 239, 241, 242, 243, 244, 245, 246, 248, 249, 250, 251, 253, 254, 255, 256, 257, 258, 259, 260, 261, 263, 264, 265, 266, 267, 268, 269, 272, 275, 276, 278, 279, 280, 281, 283, 293, 294, 295, 297, 300, 301, 307, 309, 310 HIV infection, viii, ix, x, 3, 19, 20, 21, 23, 24, 26, 28, 29, 30, 31, 32, 33, 35, 36, 38, 39, 40, 41, 42, 43, 45, 47, 48, 51, 55, 56, 57, 60, 62, 64, 65, 71, 82, 84, 85, 87, 88, 89, 90, 91, 92, 96, 98, 100, 103, 104, 106, 107, 109, 110, 114, 117, 118, 119, 121, 122, 128, 129, 130, 132, 135, 137, 138, 139, 140, 142, 143, 153, 157, 208, 212, 213, 242, 250, 251, 253, 254, 255, 257, 264, 265, 268, 283 HIV test, 26, 215, 218, 219, 224, 225, 227, 230, 231 HIV/AIDS, v, vii, ix, 1, 2, 3, 10, 13, 14, 15, 16, 23, 24, 27, 28, 29, 30, 31, 46, 64, 65, 66, 67, 69, 72, 73, 75, 83, 85, 109, 115, 131, 132, 133, 136, 142, 144, 145, 146, 147, 148, 149, 150, 151, 153, 155, 157, 160, 176, 179, 212, 214, 215, 216, 217, 219, 224, 225, 226, 227, 230, 231, 236, 237, 238, 239, 255, 266 HIV-1, xi, 19, 37, 40, 41, 43, 62, 71, 80, 81, 84, 85, 90, 91, 92, 93, 99, 100, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 138, 255, 259, 264, 265, 266, 267, 268, 269, 272, 275, 276, 278, 293, 294, 295, 297, 300, 301, 307, 309 Holland, 156, 237 homeostasis, 107, 250 homes, 163, 232 homework, 165 homogenous, 132 homology, 43, 259 homozygosity, 280, 293 honesty, 171 hospital, 12, 39, 54, 62, 72, 138, 201 hospitals, 8 host, xi, 20, 24, 25, 29, 34, 90, 101, 114, 118, 123, 141, 244, 255, 284, 295, 296, 300 hostility, 154 hotels, 137 House, 49, 51, 53, 55, 56, 65, 74, 165 household, 132, 134, 135, 142, 159, 165, 239 households, 132, 134, 135, 142, 159 human, vii, ix, 2, 3, 5, 6, 7, 9, 11, 12, 14, 15, 16, 18, 19, 21, 22, 24, 27, 29, 30, 31, 32, 33, 34, 37, 38, 43, 45, 55, 56, 74, 77, 79, 80, 83, 84, 85, 86, 88, 89, 99, 101, 102, 103, 104, 105, 106, 107, 108, 110, 112, 113, 115, 117, 118, 120, 123, 124, 125, 126, 127, 130, 131, 132, 142, 156, 235, 237, 242,

255, 256, 259, 262, 264, 266, 267, 269, 273, 275, 276, 285, 291, 292, 293, 294, 295, 297, 299, 303, 308, 310 human capital, 142 human development, 235 Human Development Report, 150 human immunodeficiency virus, vii, 19, 55, 83, 84, 85, 86, 104, 105, 106, 107, 108, 110, 112, 117, 123, 124, 125, 126, 127, 242, 256, 264, 266, 267, 269, 275, 293, 295, 297 human leukocyte antigen, 102 humanity, vii, 1, 2, 3, 5, 6, 11, 12, 16, 27, 56, 69, 77 humans, viii, xi, 8, 12, 29, 88, 90, 93, 94, 98, 107, 108, 118, 126, 250, 251, 261, 262, 264, 266, 271, 273, 287, 289, 305 humoral immunity, 12 hunting, 54 husband, 157 hydro, 242 hydrocarbon, 251 hydrocarbons, 265 hydrogen, 243 hydrogen peroxide, 243 hydrolyzed, 263 hydroperoxides, 260 hydroxyl, 243 hygiene, 6 hypercholesterolemia, 269 hypergammaglobulinemia, 253 hyperlipidemia, 255, 258 hypertriglyceridemia, 257 hypothesis, 100, 275 hypoxia, 249

I icosahedral, 278 identification, 104, 105, 114, 272, 284, 310 identity, 158, 235 ideology, 140 Illinois, 279 imbalances, 156 immune activation, x, 93, 106, 241 immune cells, 11, 89, 244 immune function, 19, 90, 91, 102, 244, 263, 269 immune response, viii, x, 11, 12, 16, 21, 25, 33, 34, 41, 42, 84, 88, 89, 90, 93, 94, 95, 96, 97, 98, 100, 101, 106, 107, 108, 109, 110, 112, 115, 117, 118, 122, 127, 244, 250, 271, 284

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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Index immune system, vii, viii, x, 3, 11, 37, 87, 88, 90, 96, 101, 104, 110, 141, 241, 243, 244, 245, 248, 249, 250, 251, 255, 261 immunity, viii, 2, 4, 12, 16, 21, 40, 42, 88, 89, 90, 94, 95, 96, 99, 100, 103, 107, 108, 109, 110, 111, 113, 115, 118, 122, 123, 243, 250, 278 immunization, 8, 85, 98, 102, 104, 109, 111, 114, 122 immunocompetent cells, 40, 41, 43 immunocompromised, x, 241, 243 immunodeficiency, viii, 83, 87, 99, 102, 103, 104, 105, 107, 109, 110, 111, 112, 113, 123, 125, 147, 242, 244, 250, 256, 264, 266, 267, 269, 273 immunogen, 11, 34 immunogenetics, 272, 290 immunogenicity, 25, 26 immunoglobulin, 12, 104, 242, 253, 268 immunoglobulin G, 104 immunoglobulins, 12 immunohistochemical, 285, 296 immunohistochemistry, 276 immunological, vii, 1, 11, 25, 37, 39, 106, 120, 122, 126, 245, 258 immunology, 4, 17, 34, 106, 110 immunomodulatory, 107 immunopathology, 34, 113 immunosuppression, 71 immunosuppressive, 278, 284 immunosuppressive agent, 278 immunotherapy, 51, 57, 58 impulsive, 234 in vitro, 37, 41, 91, 92, 97, 98, 99, 100, 114, 118, 120, 124, 138, 245, 246, 251, 255, 259, 261, 262, 303 in vivo, 37, 97, 113, 121, 122, 246, 253, 259, 263, 265, 269, 302, 307, 308 inactivation, 34, 260 inactive, 287 incentives, 65, 134, 141, 143 incidence, 2, 108, 135, 138, 282, 285, 286, 287, 288, 290, 292, 294 inclusion, 76, 159 income, 135, 139, 141, 144, 151 income inequality, 141, 151 incomes, 136, 137, 142 incubation, 32 incubation period, 32 incurable, 20, 28, 29, 30, 31, 39, 42, 132 independent variable, 233 India, 5, 143

327

Indian, 221, 279, 280 Indiana, 145 indication, 42, 159, 188 indices, 251 indigenous, 29, 156 individual action, 154 individual differences, 273 individuality, 11, 130, 267 induction, 80, 89, 90, 94, 95, 97, 98, 101, 104, 105, 107, 115, 261, 265, 269, 295, 310 inductor, 261 industrial, 164, 166 industry, 22, 64, 139, 158 inequality, 135, 136, 141 infancy, 2 infarction, 8 infection, v, viii, ix, x, 2, 3, 5, 6, 13, 16, 17, 19, 20, 21, 23, 26, 29, 30, 31, 32, 33, 39, 40, 41, 42, 43, 48, 55, 62, 70, 82, 84, 85, 87, 88, 89, 90, 91, 92, 93, 94, 96, 97, 98, 99, 100, 101, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 117, 118, 120, 121, 122, 123, 124, 125, 126, 128, 129, 131, 133, 134, 135, 138, 140, 142, 143, 153, 155, 157, 193, 194, 208, 212, 213, 216, 241, 250, 251, 253, 254, 255, 257, 260, 264, 265, 267, 268, 272, 273, 276, 278, 279, 280, 281, 284, 293, 294, 295, 297, 298, 301, 309 infections, vii, viii, 2, 12, 16, 18, 19, 20, 21, 29, 39, 40, 64, 87, 88, 91, 94, 98, 112, 131, 138, 195, 212, 243, 244, 248, 255, 257, 295 infectious, 2, 4, 7, 14, 64, 82, 88, 105, 120, 124, 132, 134, 182 infectious disease, 2, 4, 64, 82, 88, 182 infectious diseases, 2, 64, 88 infertility, 183 inflammation, x, 91, 245, 271, 279, 280, 284, 298 inflammatory, x, 110, 242, 243, 245, 257, 271, 275, 280, 284, 296, 299 inflammatory mediators, 299 inflammatory response, 296 influence, 185, 186, 192, 200, 211, 216, 217, 244, 263, 265 influenza, 8, 84 informal sector, 139, 140 informed consent, 26, 31, 56, 74 infrastructure, 24, 137, 138 inherited, 3, 304 inhibition, 98, 100, 103, 108, 110, 125, 245, 246, 249, 250, 254, 255, 257, 259, 260, 268, 292, 305, 308

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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328

Index

inhibitor, 254, 256, 268 inhibitors, 242, 255, 256, 258, 259, 261, 263 inhibitory, 96, 106, 109, 114, 254, 257, 260, 273 inhibitory effect, 254, 257, 260, 273 initiation, 118, 154, 213, 275 injection, 26, 35, 37, 50, 71, 187, 200 injections, 35, 50 injunction, 74 injuries, 38 injury, iv, 193, 194, 296 innate immunity, 90 inoculation, 98, 107, 113 insane, 29 insecurity, 139 instability, 137 institutions, ix, 15, 22, 46, 47, 130, 132, 133, 143, 154 instruments, 139 insulin resistance, 255 insurance, 122 integration, 120, 122 integrity, 11, 106, 244, 255 intellect, 36 intellectual property, 25, 144 intellectual property rights, 144 intensity, 288, 291, 302 interaction, 12, 92, 115, 120, 121, 122, 123, 133, 250, 253, 266, 278, 301, 308, 310 Interaction, 114, 226, 267 interactions, x, 59, 92, 123, 126, 155, 242, 245, 259, 269, 284 intercellular adhesion molecule, 242 interest, 167, 175, 190, 257, 263 interference, 259, 291 interferon, 93, 97, 242, 257, 273, 274, 291, 292 interferon gamma, 292 interferon-inducible protein 10, 274 interferons, 273 interferon-γ, 273 interleukin, 123, 245, 265, 273, 292, 298 interleukin-1, 298 interleukins, 112 internal locus of control, 154 internalization, 102, 127, 154, 255, 301, 302, 308, 309, 310 international, ix, 3, 15, 22, 23, 24, 25, 44, 45, 46, 47, 64, 65, 82, 129, 134 International Monetary Fund, 136, 140 internet, 30 interneuron, 310

interneurons, 301, 310 internship, 27 interpersonal relations, 156 interphase, 121 interpretation, 78 intervention, v, 39, 117, 118, 137, 139, 156, 236, 237, 284, 290, 294 interview, 58, 159, 160 intestinal tract, 93 intestine, 120, 263 intimacy, x, 135, 153, 171, 235 intimidation, 215 intramuscular injection, 35, 36, 38, 44, 50 intravenous, 12, 32, 35, 37, 71 intravenously, 38, 99 intrinsic, 120, 125 intron, 292 inventions, 3 Investigations, 265, 266, 267 investment, 133, 142, 154 Ireland, 129 iron, 244 irradiation, 289 ischemic, 286, 299 island, 133 isoforms, 262 isolation, 2, 16, 17, 24, 84, 297 isomers, 254 issues, 160, 237 Italy, 280

J Jamaica, 83, 91 January, 35, 36, 71, 76, 145, 147, 148, 149, 150 Japan, 117 Jefferson, 14 jobs, 158 John F. Kennedy, 53 Jordan, 208, 239 journalists, 13 Jun, 69 Jung, 296 justice, 74

K Kaiser Family Foundation, 179, 237 Kenya, 133, 135, 136, 137, 146, 149, 151, 235, 238

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index kidney, 10, 11, 262, 285, 299 kidney transplant, 285, 299 kidney transplantation, 299 kidneys, 8 killing, 46, 101, 205, 250 kinase, 257, 305, 308 Kinase, 242, 249 kinetics, 112, 282 King, 105, 297 knockout, 274, 289 knowledge, 156, 157, 158, 212, 235, 236, 238, 244, 264 Korea, 297 Korean, 279, 280, 285, 297, 298

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L labeling, 213 labor, ix, 129, 147, 158 labour, 133, 134, 135, 137, 139, 140, 141, 142, 144, 166, 199 labour market, 134, 137 laceration, 157 lactate level, 256 lactic acid, 255, 256 lactic acid level, 256 lamina, 92, 94 lamivudine, 242, 258, 261 land, 135, 139, 268 Langerhans cells, 91, 107, 111, 115, 118, 124, 126 Langmuir, 113 language, 3, 261 large-scale, 41 laser, 276, 302 latency, 122, 281 later life, 142 Latin America, 150 law, 132, 136, 137, 144, 211 laws, 27, 74, 158 lawyers, 21, 22 lead, 23, 30, 32, 121, 142, 156, 157, 172, 194, 244, 250, 251, 258, 259, 284 leadership, 137 learners, 179, 198, 213, 216, 221 learning, 3, 27, 30 lectin, 92, 118, 119, 120 legal, 157, 207 legislation, 72 leisure, 164, 165, 166 Leisure, 165

329

leisure time, 164, 165 lentiviral, 106, 125 lesions, 36, 138, 258, 274, 275, 286, 299 leukaemia, 16, 83 leukemic, 272 leukocyte, 120, 287 Leukocyte, 127 leukocytes, x, 123, 243, 271, 273, 284, 301, 308 liberal, ix, 130, 233 liberalization, 137, 141 liberation, 251 Liberia, 133 licensing, 10 life span, 38 lifespan, 43, 255 lifetime, 181, 213 ligand, xi, 92, 97, 254, 263, 267, 284, 289, 296, 297, 300, 301, 302, 307, 309 ligands, x, xi, 97, 98, 100, 254, 271, 272, 276, 277, 279, 284, 290, 298, 305 likelihood, 22, 138, 159 limitation, 256 limitations, 4 linear, 278 links, ix, 129, 133, 154, 299 lipid, 244, 245, 249, 251, 253, 256, 257, 258, 259, 265, 266 Lipid, 249, 264, 265 lipid metabolism, 251 lipid oxidation, 249, 265 lipid peroxidation, 251, 256, 257, 266 lipids, 253, 258 lipooxygenase, 249 lipophilic, 253 lipopolysaccharides, 97 lipoprotein, 242, 253, 259, 264, 265, 267, 268 lipoproteins, 249, 258 lipoxygenase, 249 listening, 170 Listeria monocytogenes, 255 literature, 30, 99, 156, 279, 284, 285 liver, 11, 143, 245, 256, 261, 262, 273, 280, 281, 285, 286, 292, 296, 297, 298, 299 liver disease, 281, 297, 298 liver transplant, 273, 285, 286, 292, 298, 299 liver transplantation, 285, 286, 299 living conditions, 158 local authorities, 160 localization, 145, 294, 296 location, 159, 302

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index

330

locus, 154, 267 London, 5, 37, 54, 84, 87, 145, 146, 147, 148, 149, 150, 151, 159 loneliness, 185 long period, 21 long-term, 21, 40, 84, 85, 120, 126, 127, 134, 142, 235, 285, 286, 299 loss of control, 89 love, 157, 166, 167, 168, 169, 170, 171, 174, 175, 177, 182, 183, 184, 185, 187, 188, 189, 190, 191, 192, 194, 198, 200, 203, 205, 234 low molecular weight, 245 low-density, 265, 267, 268 low-density lipoprotein, 265, 267, 268 lung, 36, 296 lungs, 251 lying, 170 lymph, 89, 90, 92, 93, 94, 95, 97, 98, 102, 108, 109, 111, 120, 121, 278 lymph node, 89, 90, 92, 93, 94, 95, 97, 98, 102, 108, 109, 111, 120, 121, 278 lymphocyte, x, 20, 21, 51, 84, 85, 100, 104, 111, 242, 245, 248, 253, 257, 264, 265, 268, 287, 296, 307 lymphocytes, viii, x, 11, 20, 36, 41, 42, 79, 80, 87, 89, 104, 106, 114, 126, 241, 245, 248, 250, 251, 253, 254, 265, 266, 268, 276, 285, 289, 301 lymphoid, 93, 102, 103, 244, 255, 276, 289 lymphoid organs, 276 lymphoid tissue, 93, 102, 255, 289 lymphoma, 278

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M machinery, 139 macrophage, x, 91, 111, 123, 242, 254, 271, 275, 284, 296, 297 macrophage inflammatory protein, x, 242, 271, 284, 296 macrophages, 19, 42, 92, 95, 97, 100, 111, 112, 118, 119, 125, 128, 243, 245, 249, 251, 255, 257, 258, 269, 276, 289 Madison, 146 magnesium, 267 magnetic, iv maintenance, 54, 90, 93, 306 maize, 142 major cities, 158 major histocompatibility complex, 11, 105, 112 malaria, 14

male, 156, 157, 159, 161, 163, 164, 185, 186, 189, 194, 198, 209, 212, 213, 215, 216, 221, 222, 232, 234 males, 155, 157, 160, 163, 165, 178, 179, 180, 188, 189, 190, 212, 213, 215, 221, 230, 231, 234, 236 malicious, 44 malnutrition, 244, 268 mammals, 261, 301, 302 management, 53, 60, 72, 265, 295 Manhattan, 8 manipulation, 96 manufacturing, 73 marginal product, 140 marital status, 157 market, 132, 139, 140, 143, 144 market access, 144 marketing, 56 markets, 142 marriage, 134, 155, 157, 172, 185, 235, 237 marriages, 134 marrow, 292 Maryland, 14, 145 masculinity, 139, 157, 191 mass, 154, 239 mass communication, 46, 47 mass media, 154, 239 material resources, 55, 56 maternal, 12 mathematical, 255, 295 mathematics, 3 maturation, 20, 114, 118, 119, 124, 125 mean, 156, 178, 179, 234 Mean, 178, 179 meanings, x, 153, 155 measles, 2, 12, 62 measurement, 273, 282 measures, 4, 6, 7, 157, 158 mechanical, iv media, 47, 62, 67, 77, 154, 219, 239 median, 136, 179, 234, 282 mediation, 301 mediators, 112, 113, 237, 268, 284 medical care, 138 medical school, 33 medical student, 50, 53 medication, 23, 26 medications, 255 medicine, 6, 17, 30, 44, 45, 74, 117 Medline, 261 medusa, 303

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

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Index membership, x, 153 membrane permeability, 250 membranes, 256 memory, 21, 84, 85, 90, 93, 96, 112, 122, 212, 276, 282, 295, 305 men, 24, 28, 32, 82, 91, 114, 134, 135, 138, 141, 157, 158, 189, 190, 191, 194, 195, 212, 234, 237 menarche, 196 menstruation, 196, 197, 200, 201 Merck, 46, 82, 83, 90 mesangial cells, 257 mesentery, 33 mesoderm, 301, 302 meta-analysis, 261 metabolic, 245, 256, 257, 263, 266, 267 metabolic acidosis, 256 metabolic disorder, 267 metabolic rate, 245 metabolism, 251, 258, 259, 261, 262, 263, 268, 269 metabolite, 265 metabolizing, 261 methodology, 251 mice, 8, 94, 95, 96, 103, 105, 256, 273, 274, 285, 289, 292 microbes, 5, 6, 12 microbial, 95, 114 Microbial, 83, 84 microglia, 19, 276 micronutrients, 243, 245, 248, 257, 264 microorganisms, 251 micro-organisms, 2 microparticles, 111 microsatellites, 276 microscopy, 255 microspheres, 96 migrant, ix, 129, 133, 134, 135, 144, 147, 158 migrants, 139, 158 migration, x, xi, 89, 94, 133, 137, 158, 271, 284, 289, 300, 301, 302, 303, 304, 305, 307, 308, 309, 310, 311 military, 45, 137 milk, 5, 6 Millennium, 147, 148, 151 mimicking, 121 minerals, 144 mines, 139, 158, 236 mining, 135, 139, 158 minorities, 155 minority, 213 minors, 207

331

miscarriage, 100, 199 misconceptions, 197, 212 mitochondria, 251, 253, 254, 256, 264, 269 mitochondrial, 242, 249, 251, 255, 256, 258, 265, 267, 269 mitochondrial abnormalities, 258 mitochondrial DNA, 242, 249, 255, 256, 258, 265, 267 mitogen, 273, 289 mitosis, 20 mitotic, 11 mobility, 118, 211 modalities, 25, 144 model system, 307, 308 models, 134, 245, 255, 288 modernisation, 143 modulation, 97, 109, 249, 289, 310 molecular changes, 267 molecular mass, 276 molecular weight, 20, 92, 245 molecules, 19, 91, 92, 94, 96, 97, 98, 99, 103, 110, 111, 112, 120, 121, 122, 126, 250, 284, 290, 307 momentum, 14 money, 13, 46, 76, 83, 137, 159, 167, 168, 169, 171, 172, 177, 178, 182, 190, 202, 208, 213, 227, 229, 230, 233, 235, 237 Money, 226 monkeys, 8, 9, 10, 90, 93, 98, 102, 108, 110 monoclonal, 98, 284, 289 monoclonal antibodies, 98 monoclonal antibody, 284, 289 monocyte, 92, 118, 119, 125, 249, 254, 265, 269, 275, 285, 297, 298 monocyte chemoattractant protein, 275, 298 monocyte chemotactic protein, 285 monocytes, 19, 42, 91, 95, 102, 118, 119, 125, 245, 250, 251, 257, 258, 276, 289, 297 mononuclear cell, 100, 111, 251 mononuclear cells, 100, 111, 251 mononucleosis, 20 monopoly, 29 Monroe, 148 Moon, 297 morbidity, vii, 1, 4, 248, 274 morning, 200 morphogenesis, 308 morphological, 301 morphology, 36, 255, 267 mortality, vii, x, 1, 4, 138, 141, 248, 257, 261, 265, 267, 271, 272, 284, 286

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index

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332

mortality rate, 4, 257 mother cell, 20 mothers, 12, 13, 18, 41, 42, 163, 165, 221 moths, 19 motion, 58 motivation, 208 motives, 185 motor neurons, 301 mouse, 94, 106, 113, 118, 274, 284, 302, 305 mouse model, 106, 113, 274, 284 mouth, 177 movement, 133, 164, 301 Mozambique, 133, 140, 142, 147, 225, 237 mucosa, 89, 93, 94, 96, 97, 104, 105, 107, 111, 243 mucosal barrier, viii, 87, 89 mucous membrane, vii multicellular organisms, 250 multinational companies, 56 multiple births, 79 multi-stage sampling, 159 multivariate, 283, 288 mumps, 2, 12 murder, 74, 202, 205, 206 murine model, xi, 245, 255, 271, 285, 288 murine models, xi, 245, 271, 285, 288 muscle, 196, 197, 249, 258, 305, 307, 308, 309, 310 muscle cells, 249, 258 muscles, 301, 305, 306, 307 music, 140, 165 Muslim, 135 Muslims, 143 mutant, 254, 303, 304, 305 mutants, xi, 19, 34, 89, 300, 302, 303 mutation, viii, xi, 34, 87, 89, 98, 140, 245, 254, 272, 273, 275, 276, 277, 281, 282, 284, 286, 287, 288, 289, 291, 293, 294, 297, 298, 303 mutations, 43, 276 mutual, 166, 167, 198, 203 Mycobacterium, 120 myeloid, 118, 120, 124 myelotoxic, 256 myoblasts, 306 myocytes, 306 MyoD, 305 myogenesis, 302, 306, 307, 309

N N-acety, 245, 249, 254, 256 Namibia, 13

narratives, 237 nation, 14, 132 national, 14, 15, 23, 57, 140, 141, 143, 144, 179, 181, 213, 216, 221, 237, 238, 239 national income, 141, 143 National Institutes of Health, 15, 82, 143 nationality, 27 natural, 4, 19, 29, 33, 41, 85, 88, 90, 92, 93, 97, 98, 100, 111, 120, 126, 154, 156, 245, 250, 254, 263, 267 natural killer, 97, 245, 250 natural killer cell, 97, 245 nausea, 243 neck, 12 necrosis, 264 needles, vii, 13, 138 needs, 159, 167, 168, 171, 244, 259 negative emotions, 197 neglect, ix, 130 negotiating, 239 negotiation, 25, 225 Nelson Mandela, 179 nematode, 266 neocortex, 310 neoliberal, ix, 130, 131, 132, 136, 141, 142 neoliberalism, 136, 141 neonates, 12 nephropathy, 285, 299 network, 84, 132, 133, 135, 144, 245 networking, 236 networks, 211 neural crest, 301 neural development, 301, 308 neural tissue, 310 neuronal cells, 301 neurons, 276, 301, 305 neuropathy, 255 neutralization, 122, 245 neutrophil, 118 neutrophils, 257 New England, 149, 265, 269 New World, 5 New York, iii, iv, 8, 10, 14, 15, 83, 84, 86, 110, 111, 144, 145, 146, 147, 148, 149, 150, 151, 235, 238, 296 newspapers, 45 next generation, viii, 87, 96, 108, 126, 302 niacin, 248 Nigeria, 1, 3, 19, 22, 27, 28, 29, 32, 37, 40, 42, 46, 47, 48, 49, 50, 51, 52, 54, 55, 56, 64, 65, 66, 67,

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index 68, 69, 70, 71, 72, 73, 74, 77, 79, 83, 84, 85, 132, 133, 143, 144, 148, 239 Nile, 279, 297 nitric oxide, 243 nodes, 89, 94, 97 noise, 9 non invasive, 251 non-human, 93, 103, 106, 109, 111 non-human primates, 93, 106, 109, 111 non-myeloablative, 288, 289 normal, 2, 3, 11, 12, 36, 37, 38, 39, 40, 41, 43, 44, 51, 56, 80, 102, 108, 172, 200, 201, 243, 245, 253, 256, 259, 265, 274, 275 normalization, 245 norms, 137, 156, 208, 225 North America, 166 notochord, 303, 304, 306 nuclear, x, 44, 119, 154, 241, 242, 253, 254, 259, 269, 305 nuclear family, 154 nuclear receptors, 269 nuclei, 259 nucleoside reverse transcriptase inhibitors, 242, 255, 258 nucleus, 20, 34, 259 nursing, 44 nutrient, x, 241, 244, 264, 265 nutrition, 138 nutritional deficiencies, x, 242 nutritional supplements, 144

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O observations, 59, 60, 100, 274 occupational, 208, 225, 226, 233 Ohio, 147 oil, 144 old age, 203 older people, 217 old-fashioned, 17, 18 open-mindedness, 3 opportunist, 243, 244, 248, 257 opposition, 7, 46, 154 optimism, 32, 51 optimization, 106 oral, vii, 9, 10, 36, 92, 105, 106, 107, 108, 109, 111, 177, 198, 206, 223, 224, 226, 228, 229, 231, 232, 234, 235, 243, 263, 266 oral cavity, 92 oral contraceptives, 198, 206

333

oral leukoplakia, 36 organ, 11, 287, 289, 301 organelle, 255 organism, 88, 190, 244, 263 organization, 69, 131, 155 organizations, ix, 65, 129 orgasm, 169, 173, 181, 185, 186, 195 orientation, 191 orthodox, 32 oscillations, 309 Ottoman Empire, 5 outpatient, 12, 35, 36, 43, 51, 55, 56, 57, 58, 62, 71 overproduction, x, 241, 245, 251, 257 oxidation, 249, 253, 255, 257, 258, 261, 262, 263, 265, 266, 267, 268 oxidative, x, 241, 243, 244, 245, 246, 248, 250, 251, 253, 256, 263, 264, 265, 266, 268 oxidative damage, 253, 256, 264 oxidative stress, x, 241, 243, 244, 245, 246, 248, 250, 251, 253, 256, 263, 264, 265, 266, 268 oxide, 243 oxygen, x, 241, 243, 245, 256, 257, 258, 269 Oxygen, 266

P pain, 185, 186, 193, 194, 196, 197, 201 pancreatitis, 255 pandemic, viii, ix, 2, 3, 11, 19, 22, 24, 31, 48, 51, 55, 69, 87, 88, 117, 130, 131, 133, 136, 138, 141, 143, 155, 297 paper, viii, xi, 5, 66, 71, 88, 90, 129, 146, 148, 272 Paper, 144, 148, 149 paracrine, 245 paradoxical, 137 paralysis, 8 parental control, 154, 180 parenteral, 108 parents, 8, 9, 28, 76, 154, 157, 159, 162, 167, 168, 169, 170, 175, 176, 182, 198, 199, 201, 202, 204, 205, 208, 210, 226, 229, 230, 232, 233 Paris, 7 particles, 20, 89, 91, 99 partnership, 182, 183, 217 Partnership, 182 partnerships, 131 passive, 12, 157 pasteurization, 6 pastoral, 142 patents, 144

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334

Index

paternal, 79 pathogenesis, xi, 40, 91, 102, 110, 112, 245, 265, 269, 272, 276, 284, 296 pathogenic, 29, 112, 113 pathogens, 112 pathophysiology, 260 pathways, 90, 123, 124, 236, 264 patients, x, xi, 6, 7, 28, 31, 32, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47, 51, 56, 57, 60, 70, 71, 73, 74, 75, 76, 78, 79, 81, 89, 92, 96, 100, 104, 113, 138, 241, 243, 244, 245, 246, 248, 250, 251, 253, 255, 256, 257, 258, 259, 260, 261, 263, 264, 265, 266, 268, 269, 272, 273, 274, 275, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 290, 291, 292, 293, 297, 298 patriotism, 55, 75 patterning, 308, 311 pediatric, 285, 298 peer, 45, 154, 156, 185, 211, 217, 232, 234 peer group, 154, 217 peer review, 45 peers, 6, 164, 216, 217, 230, 231, 232, 233 penetrance, 273 penis, 160, 177, 193, 194 pentane, 251, 266 people living with HIV/AIDS, 22, 25, 212, 255 Pepfar, 144 peptide, 20, 95, 98, 104, 114 peptides, 34, 98, 111, 121 per capita, 143 perception, 59, 214, 216, 219, 230, 231, 238 perceptions, 232 perinatal, 85, 110 Peripheral, 43, 295 peripheral blood, 35, 100, 125, 273, 282, 288, 292, 294 peripheral blood lymphocytes, 273 peripheral blood mononuclear cell, 100, 273 peripheral nervous system, 301 peripheral neuropathy, 255 permeability, 250, 251 permit, 50 peroxidation, 251, 253, 256, 257, 266 peroxide, 243 peroxynitrite, 249 personal, 8, 30, 39, 45, 48, 57, 66, 76, 132, 135 personal responsibility, 132 personhood, 207 perspective, 159, 235, 236, 264 pertussis, 2, 12

Peru, 83, 91 P-glycoprotein, 263, 266 phagocytic, 251 pharmaceutical, viii, 15, 23, 46, 65, 87, 143 pharmacists, 32 pharmacokinetics, 268 pharmacologic agents, 261 phenotype, 93, 106, 119, 294, 302, 303, 304 phenotypes, 118, 293 Philadelphia, 84 phone, 9 phosphate, 256, 269 phosphorylation, 99, 249, 254, 255, 257, 301 Phosphorylation, 266, 308 physical abuse, 159, 170, 183 physical force, 211 physicians, 8, 38, 39, 70, 290 Physicians, 27, 44 physiological, 25, 251 pig, 71 placebo, 2, 26, 91, 248, 253 placenta, 12, 29, 40 plague, 4, 5 planning, 183, 200, 235 plants, 98 plasma, 11, 20, 21, 33, 41, 89, 90, 243, 244, 248, 251, 253, 258, 262, 264, 274, 275, 278 plasma levels, 245 plasma membrane, 275, 278 plasmid, 95, 110, 115 plastic, 3 plasticity, 118, 310 platelet, 33, 249, 259, 260, 265, 267, 268, 269 platelet aggregation, 249, 259, 267, 268, 269 platelets, 33, 260 play, x, 8, 42, 89, 92, 94, 118, 121, 122, 165, 197, 237, 244, 271, 273, 275, 284, 289, 302 pleasure, ix, x, 135, 153, 157, 158, 185, 215 point mutation, 276 Poland, 271, 290 polarity, 301 polarization, 278, 302 polarized, xi, 271, 285 policy, 235 polio, 2, 7, 8, 9, 10, 12, 13, 14, 15, 62 poliovirus, 8, 10, 105 political, ix, 13, 44, 88, 131, 132, 134, 135, 136, 138, 143, 153, 158, 238 political instability, 138 politicians, 13

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Index politics, 27, 44, 131, 134, 135 polycyclic aromatic hydrocarbon, 265 polygamous marriages, 134 polymerase, 43, 255, 258, 269, 295, 298 polymerase chain reaction, 295, 298 polymers, 95 polymorphism, v, xi, 124, 271, 272, 273, 274, 275, 278, 279, 282, 283, 284, 285, 286, 287, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299 polymorphonuclear, 243 polyunsaturated fat, 251 polyunsaturated fatty acid, 251 pools, 20 poor, x, 83, 137, 138, 141, 143, 158, 215, 241, 243, 263 population, 2, 3, 25, 40, 80, 85, 93, 101, 105, 124, 133, 141, 158, 166, 212, 257, 282, 297 Population, 236, 238 poverty, ix, 130, 133, 135, 136, 137, 138, 139, 140, 141, 142, 144, 158, 211 Poverty, 158 poverty rate, 141 power, 4, 27, 38, 132, 134, 139, 141, 144, 156, 157, 237 powers, 68 practical knowledge, 50 preclinical, 89 precursor cells, 307, 308 prediction, 5, 8, 14, 18, 84 predictive marker, 290 predictors, 208, 211, 230, 231, 268, 292 preference, 39 pregnancy, vii, 11, 12, 38, 42, 155, 160, 176, 182, 183, 185, 196, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 216, 219, 225, 227, 229, 230, 231, 237, 238, 239 pregnancy test, 200, 201 pregnant, 26, 42, 170, 171, 175, 176, 182, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 208, 213, 225, 226, 227, 230, 231, 248 prejudice, 71 premature infant, 12 preparation, iv, 17, 18, 34, 38, 61, 84, 165 preservative, 38 preservatives, 2 president, 74 President Clinton, 15 pressure, 143, 172, 185, 204, 209, 210, 211, 234 prestige, 185 Pretoria, 148, 153, 159, 237, 238, 239

335

prevention, ix, 15, 23, 26, 72, 89, 102, 108, 114, 130, 131, 132, 134, 139, 141, 143, 155, 156, 158, 218, 228, 235, 236, 237, 238, 249, 257, 258, 259 preventive, vii, 1, 11, 15, 17, 18, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 36, 37, 42, 47, 57, 59, 63, 66, 69, 70, 71, 77, 81, 89, 157 prices, 143, 144 primary, 159, 193, 208, 221 primary care, 208 primary caregivers, 208 primary school, 159 primate, 103, 105, 106, 111, 125 primates, 89, 109 priming, 103 primordial germ cells, 311 priorities, 32 private, ix, 8, 25, 32, 57, 65, 72, 129, 140, 156, 163, 195, 210 private sector, 25, 65 privatization, 136 pro-apoptotic protein, 268 probability, 15, 207 procedures, 160 processing pathways, 105 producers, 139, 140, 273, 275 production, x, 5, 8, 9, 12, 17, 18, 26, 32, 34, 38, 40, 41, 43, 80, 94, 95, 96, 98, 102, 106, 107, 112, 114, 118, 120, 121, 241, 243, 244, 245, 248, 249, 251, 254, 255, 256, 257, 258, 260, 265, 269, 273, 274, 275, 281, 289, 291, 292, 296 productivity, 119, 122 profession, 16, 27, 44, 71 profit, 143 profitability, 132, 135, 137 profits, 143 progenitor cells, 288, 292, 301, 305, 310 progenitors, 305, 307, 309, 311 progeny, 122 prognosis, 235, 294 prognostic marker, v, 271, 291 prognostic value, 253, 290 programming, 154 programs, 156 progressive, 19, 144, 243 pro-inflammatory, 94,245, 249, 274, 284, 289 proinflammatory chemokines, 289 proliferation, 93, 96, 103, 107, 110, 244, 249, 257, 259, 264, 289, 309 promote, 143, 171, 245, 309

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Index

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336

promoter, 258, 261, 276, 279, 280, 291, 294, 296, 298 promoter region, 261, 276 pro-oxidant, 264 propagation, 102 property, iv, viii, 117, 154 prophylactic, 8, 284 prophylaxis, 26, 288, 290 protease inhibitors, 242, 255, 258, 259, 263, 266, 267 protection, viii, 2, 6, 12, 23, 25, 30, 34, 37, 41, 42, 46, 88, 89, 90, 92, 94, 95, 97, 99, 100, 102, 103, 104, 105, 107, 108, 109, 111, 113, 115, 122, 159, 212, 217, 248, 257, 258, 275, 278, 279, 294, 297 protective mechanisms, 25 protective role, 106, 288, 289 protein, xi, 16, 17, 18, 20, 26, 99, 105, 106, 109, 110, 111, 113, 120, 126, 127, 141, 242, 243, 245, 249, 254, 255, 257, 258, 259, 260, 264, 267, 272, 275, 276, 278, 279, 295, 305, 308 protein kinase C (PKC) , 249, 254, 257, 258, 260, 264 proteins, 17, 18, 19, 20, 29, 31, 34, 43, 99, 102, 103, 109, 114, 120, 125, 250, 251, 258, 259, 268, 278, 284, 302, 309 Proteins, 291 proteolytic enzyme, 2 protocol, 7, 10, 25, 26, 27, 31, 70, 160 proxy, 140 psyche, 3 psychological, 25, 167 psychologists, 142 psychology, 235 psychosocial, 236 Pub Med, 88 public, 9, 13, 14, 28, 45, 59, 65, 74, 77, 136, 137, 138, 141, 143, 144, 239 public health, 9, 45, 138, 141, 144, 239 public money, 143 public relations, 9 publishers, 47 Puerto Rico, 83, 91 pupils, 159, 161, 212, 215, 238 purification, 2 pus, 5, 6

Q qualifications, 160 quality of life, viii, 87, 255

questionnaire, 180 quinone, 249, 259 quota sampling, 159

R rabies virus, 7 race, 5, 6, 18, 27, 46, 80, 221, 263 radar, 3 radical, 243, 253 radical formation, 255 radio, 165 radiological, 36 radium, 8, 10, 14, 15 random, 99 range, 19, 132, 244, 245, 249, 308 Rantes, x, xi, 105, 107, 243, 248, 254, 255, 265, 268, 271, 272, 275, 278, 279, 281, 284, 286, 289, 295, 297, 298, 299 rape, 130, 159, 190, 192, 210 rash, 293 rat, 106, 256, 267, 269, 305, 309 rational, 156 rats, 8, 265 raw material, 34, 38 reactive oxygen, x, 241, 243, 269 reactive oxygen species, x, 241, 243, 269 reactivity, 78, 80, 81, 275 reading, xi, 165, 272, 277, 307 real time, 273 reality, 131, 137, 190 real-time, 285, 295, 298 reasoning, 3, 28 recall, 50, 58, 78 reception, 73, 215 receptors, iv, viii, 12, 19, 87, 91, 92, 100, 105, 106, 107, 109, 111, 118, 119, 123, 126, 245, 249, 258, 269, 284, 285, 301, 302, 303, 304, 310 recognition, 12, 40, 41, 64, 65, 112, 121, 132, 134 reconstruction, 144 recovery, 96, 279 recreational, 144 rectum, 91, 92, 94, 97 recurrence, 260 redistribution, 144, 258, 295 redox, 245, 250 reduction, 26, 142, 245, 246, 248, 249, 251, 256, 257, 259, 261, 263, 286, 306 reflection, 131 reforms, 136

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Index regenerate, 245 regeneration, 107, 305 regional, 23, 25, 89, 90, 92, 94, 95, 120, 133, 134, 135, 136 registered nurses, 9 regression, 208, 219, 230, 231, 233, 283, 288 regression analysis, 208, 283, 288 regular, 42, 134, 158, 161, 198, 216 regulation, 91, 99, 100, 101, 109, 249, 253, 257, 258, 268, 301, 304, 305, 306, 308 regulations, 182 regulators, 306 rejection, 11, 202, 272, 285, 286, 287, 289, 299 relapse, 272, 288 relationship, x, 133, 154, 156, 157, 160, 161, 162, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 182, 183, 184, 187, 188, 189, 191, 192, 193, 198, 199, 201, 203, 204, 205, 208, 210, 213, 214, 215, 217, 219, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 241, 245, 261, 273, 281, 283, 287, 288 relationships, 134, 140, 154, 155, 157, 158, 159, 160, 161, 165, 169, 171, 172, 175, 188, 191, 192, 193, 215, 235, 273, 275, 288 relatives, 154, 162, 209 relativity, 45 relevance, 23, 110, 254, 262, 296 religion, 27, 192, 202, 205, 206, 223, 227 religious, 132, 185, 202, 208, 222, 223, 228, 230, 231, 233 religious belief, 202 religious beliefs, 202 renal, 35, 285, 286, 287, 289, 297, 299 repair, 253 replication, x, 21, 41, 90, 92, 97, 98, 99, 100, 101, 102, 104, 106, 114, 119, 121, 122, 124, 125, 126, 128, 138, 241, 245, 246, 248, 249, 254, 255, 256, 266, 269, 279 report, 155, 198, 205, 206, 209, 234, 238, 239 repression, 234 reproduction, 134, 135, 139 reputation, 188 research, iv, vii, ix, x, 1, 4, 5, 8, 9, 11, 13, 14, 15, 16, 21, 22, 23, 24, 25, 27, 28, 29, 32, 44, 47, 48, 54, 55, 56, 57, 58, 64, 65, 69, 70, 71, 75, 77, 82, 83, 94, 110, 123, 142, 143, 153, 155, 156, 158, 159, 160, 236, 237, 238, 241, 243, 245, 248, 255, 256, 263, 264, 307 research and development, vii, 1, 15, 27, 28, 56, 65, 75, 83, 143, 150

337

researchers, vii, 1, 15, 17, 18, 19, 20, 31, 37, 44, 46, 47, 71, 82, 83, 159, 244, 253, 302 reserves, 135 reservoir, 92 reservoirs, 5, 89, 255 residential, 211 residues, 301, 310 resistance, viii, 13, 85, 87, 90, 94, 98, 100, 103, 106, 111, 114, 120, 122, 125, 156, 215, 255, 267, 293, 294 resolution, 307 resources, viii, 1, 14, 24, 47, 48, 51, 57, 58, 69, 71, 141, 142 respiratory, 93, 244, 258 response, 235, 237 responsibilities, 32, 155 responsibility, 154, 198, 202, 208, 213, 233 responsiveness, 273, 293 restoration, 30, 93, 110, 269 restructuring, 133 retention, 267 retina, 245 retinoic acid, 259 retired, 55 Retroviral, 125 retrovirus, 19, 120 retroviruses, 19, 110 returns, 141 reverse transcriptase, 19, 29, 242, 255, 256, 258, 266 revolutionary, 14 riboflavin, 256 ribose, 269 risk, ix, x, 6, 16, 26, 34, 70, 82, 88, 91, 98, 100, 132, 133, 134, 135, 136, 137, 138, 141, 146, 153, 155, 156, 157, 158, 195, 208, 211, 212, 213, 214, 216, 219, 225, 227, 228, 236, 237, 238, 257, 258, 261, 268, 272, 273, 274, 275, 281, 282, 283, 285, 286, 287, 288, 289, 290, 291, 292, 293, 295, 296, 298, 299 risk assessment, 290 risk aversion, 141 risk factor, 208, 268 risk perception, 214, 216, 219 risk society, 136 risks, 25, 26, 139, 156, 217, 235, 239, 280 rodents, xi, 300 Rome, 150 room temperature, 2 royalties, 25 royalty, 171

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Index

338 rubella, 2, 12 rural, 134, 135, 142, 154, 158, 159, 198, 212, 213, 215, 223, 224, 225, 234, 237, 238 rural communities, 154 Russia, 7 Rwanda, 133, 144

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S sadness, 27 safe drinking water, 88 safeguards, 25 safety, x, 5, 6, 23, 25, 26, 31, 33, 35, 71, 82, 141, 153 saliva, 92, 111, 212 sample, 62, 78, 81, 159, 160, 162, 178, 179, 206, 221, 226, 232, 234, 236 Sample, 159, 221 sampling, 21, 80, 81, 159 sand, 76 sanitation, 88, 138 sarcoidosis, 275 Sarin, 297, 298 satellite cells, 305 satisfaction, 32, 190, 195 scalar, ix, 130, 131, 134 scarcity, 139 scavenger, 92, 249, 258, 269 schistosomiasis, 138 school, 9, 52, 136, 154, 159, 161, 162, 163, 167, 169, 174, 175, 178, 179, 180, 181, 182, 183, 185, 197, 198, 199, 202, 204, 205, 206, 208, 210, 211, 212, 213, 215, 219, 223, 228, 234, 235, 236, 237, 238, 239 school work, 175 schooling, 159, 176, 202, 203, 205, 221, 222, 233 science, 2, 13, 14, 15, 17, 44, 45, 140 scientific, 2, 3, 9, 11, 13, 14, 15, 16, 17, 19, 23, 24, 25, 26, 31, 45, 46, 59, 60, 64, 66, 69, 70, 71, 77, 88, 160 scientific community, 14, 88 scientists, 3, 5, 6, 13, 14, 15, 17, 21, 22, 32, 45, 47, 83 search, vii, 1, 2, 13, 15, 19, 63, 64, 65, 83, 88, 99, 110, 261, 279, 285 searching, vii, 1 secondary, 159, 179, 208, 212, 215, 219, 221, 223, 224, 225, 228, 233, 234, 237, 238, 239 secondary education, 221, 223, 234 secondary school students, 228, 237, 238, 239

secret, 29, 45 Secretary-General, 69 secrete, 254, 279 secretion, 12, 93, 94, 96, 97, 245, 257, 258, 259, 265, 273, 279 secrets, 27, 167 secular, 157, 180 security, 142 segmentation, 106 selenium, 133, 244, 249, 256, 257, 266 self, x, 153, 157, 185, 233 Self, 223, 238 self limiting, 20 self-employed, 233 self-organizing, 308 semen, vii, 112, 114 semi-structured interviews, 160 Senate, 56 Senegal, 132 sensing, 301, 302 sensitivity, 112 separation, 131 series, 67, 160, 275 serine, 303 serum, x, 11, 21, 41, 62, 82, 98, 100, 104, 110, 134, 241, 243, 253, 256, 268 serum albumin, 41 services, iv, 139, 235 settlements, 158 severity, 12, 82, 143, 261, 287, 288, 296, 297, 298 sex, vii, ix, x, 13, 24, 41, 82, 91, 100, 107, 108, 134, 135, 137, 138, 139, 140, 143, 153, 154, 155, 156, 157, 158, 161, 163, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 181, 182, 183, 185, 187, 188, 189, 190, 191, 192, 194, 195, 197, 198, 200, 204, 205, 206, 208, 209, 210, 211, 213, 215, 216, 217, 219, 221, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 234, 235, 236, 237, 238, 239, 283, 288 sex differences, 191, 239 sex role, 188, 191 sex roles, 188, 191 sexual, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 169, 170, 171, 172, 173, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 202, 208, 209, 210, 211, 213, 214, 215, 216, 217, 218, 219, 220, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239 sexual abuse, 182, 209

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Index sexual activities, 157, 163, 178 sexual activity, viii, x, 87, 138, 153, 154, 155, 157, 158, 173, 179, 180, 181, 185, 213, 234 sexual behavior, 156, 157, 180, 211, 216, 217, 232, 234 sexual behaviour, ix, 131, 132, 153, 155, 158, 181, 213, 217, 235, 236, 237, 238, 239 sexual contact, 120, 130, 136, 138, 218 sexual experiences, 160, 209 sexual harassment, 160, 209, 210 sexual health, 235, 237, 238 sexual identity, 235 sexual intercourse, 88, 100, 155, 157, 160, 162, 163, 169, 170, 171, 172, 173, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 193, 194, 195, 196, 202, 209, 213, 214, 215, 216, 218, 220, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235 sexual orientation, 191 sexual violence, 211 sexuality, 131, 155, 156, 157, 158, 160, 165, 167, 168, 173, 180, 182, 183, 185, 187, 188, 191, 207, 208, 212, 226, 228, 232, 233, 234, 235, 236, 237, 238, 239 sexually transmitted disease (STD), 13, 58, 59, 60, 61, 91, 137, 140, 149, 157, 182, 195, 212, 215, 216, 238, 239 sexually transmitted infections, 26, 138 SH, 68, 84, 296, 297, 298 shape, 134, 301 shares, 259 sharing, 171, 212 sheep, 3 shock, 103, 109, 273 shores, 29, 139 short period, 38, 101 short-term, 139, 191 shoulders, 17, 33 shy, 190 SI, 102, 106, 113 sibling, 288, 291 siblings, 164, 169, 199, 221, 222 side effects, 43, 88, 243, 255, 256, 259, 263 Sierra Leone, 133 sign, 158, 188 signal transduction, 257 signaling, xi, 96, 102, 125, 244, 266, 268, 300, 301, 302, 303, 305, 306, 308, 309, 310 signaling pathway, 96, 125, 306, 309 signaling pathways, 96

339

signalling, xi, 99, 112, 300, 309 signals, 95, 99, 301, 307 signs, 7, 35, 36, 62 silicon, 3 silver, 196 similarity, 259 Singapore, 300, 307 single nucleotide polymorphism, 276, 292 sites, viii, 84, 88, 89, 91, 93, 94, 96, 106, 125, 159, 245, 272, 273, 279, 301, 308 situation, 159, 168, 192, 201, 203, 205, 206, 213, 214 skeleton, 301 skills, 5 skin, 4, 5, 6, 118, 196, 215, 274, 275, 293, 296 slavery, 136, 137 sleep, 33, 139, 168, 181, 190, 194, 195, 197, 217, 219 smallpox, 4, 5, 6, 12, 13, 29, 45 smokers, 221 smoking, 170, 174 smooth muscle, 249, 258, 276 SNP, 285 soccer, 165 social, ix, x, 21, 22, 25, 26, 27, 72, 131, 132, 134, 135, 136, 137, 139, 140, 142, 143, 144, 145, 146, 149, 153, 154, 155, 156, 158, 207, 208, 211, 234, 236, 237 social capital, 140, 142 social change, 143 social class, 136 social construct, 155 social context, 145, 236, 237 social control, 137, 156, 234 social fabric, 137 social identity, 146 social life, 154 social norms, 156 social organization, 155 social problems, 237 social standing, 27 social support, 211 social support network, 211 socialism, 141 socialization, 142, 154 socially, ix, 135, 153, 156, 208 society, 59, 131, 132, 142, 148 socioeconomic, 233 socio-economic status, 159, 211 sociological, 88

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340

Index

SOD, 243, 251, 255, 257 soft drinks, 45 software, 283, 295 soil, 133, 138 solidarity, 144, 154 solutions, 34, 143 Somalia, 5 Sonic hedgehog, 308, 309, 310 sores, 5, 194 sorting, 309 South Africa, v, 13, 83, 91, 133, 134, 135, 138, 139, 140, 141, 142, 145, 146, 147, 148, 149, 151, 153, 154, 157, 158, 162, 178, 179, 180, 181, 185, 198, 208, 211, 212, 213, 215, 216, 221, 225, 232, 234, 235, 236, 237, 238, 239 SP, 102, 113, 293, 297, 298 spatial, 131, 132, 133, 137, 140 specialisation, 104 specialists, 131 species, x, xi, 93, 99, 112, 122, 137, 241, 243, 245, 256, 257, 261, 266, 267, 269, 300 specificity, 261, 263 speech, 68 speed, 13, 71 spermatozoa, 100, 110, 112 spinal cord, 7 spirituality, 235 spleen, 33, 296 sponsor, 24 sports, 164 spouse, 42, 135 SR, 249, 258, 285, 293 stability, 172 staff, 223 stages, x, 20, 22, 26, 39, 90, 94, 125, 212, 241, 248, 251, 257, 259, 301 stakeholders, 25 standard error, 44 standard model, 154 standards, 17, 23, 64 Standards, 79, 81 stasis, 306 statistical analysis, 43, 295 statistics, ix, 129 stele, 2 stem cell transplantation, 274, 278, 285, 286, 290, 291, 292, 295, 296, 298 stem cells, 118, 119, 272, 274, 287 stemness, 306 stereotypical, 211

sterile, 26 sterilization, 71 steroids, 261 stigma, 26, 39 stigmatization, 19, 39 stigmatized, vii, 1, 28, 33, 42 stimulus, 251 STIs, 26, 171, 182, 192, 195 stock, 38 stockpile, 14 stomach, 196, 197, 201 storage, 38, 259 strain, 9, 10, 19, 34 strains, 9, 10, 34, 65, 84, 88, 89, 91, 105, 124, 125, 275 strategic, 54 strategies, 15, 23, 25, 40, 88, 89, 94, 100, 103, 131, 140, 156, 188, 191, 272 stratification, 158 strength, 154 stress, x, 194, 201, 204, 206, 241, 243, 244, 245, 246, 248, 250, 251, 253, 256, 263, 264, 265, 266, 268 stromal, 102, 243, 301, 307, 310 stromal cell-derived factor-1, 307 strong force, 14 structural adjustment, 132, 134, 135, 136, 140 structural adjustment programmes, 132, 136, 140 structural gene, 105, 293 students, 53, 156, 161, 180, 181, 208, 215, 228, 235, 236, 237, 238, 239 study, 159, 160, 169, 176, 179, 180, 196, 197, 198, 202, 204, 205, 206, 213, 215, 221, 239 submucosa, 120 sub-Saharan Africa, vii, ix, 1, 3, 11, 13, 69, 88, 129, 130, 134, 136, 143, 145, 150, 181, 212, 235, 236, 237 Sub-Saharan Africa, 134, 136, 138, 145, 149, 237 subsidies, 25, 136 substance abuse, 24 substance use, 160, 220 Substation, 57, 58, 77 substrates, 263 suburbs, 8 subventricular zone, 310 Sudan, 133 suffering, ix, 7, 129, 176, 199 suicidal, 8 suicide, 171, 205 sulfatide, 103

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Index sulphate, 92 Sun, 69, 293, 296, 308 Sunday, 58, 67, 69 superego, 154 supernatural, 154 superoxide, 243, 251, 255, 257, 265, 268, 269 superoxide dismutase, 243, 251, 256 supervision, 232 supplements, 246, 265 supply, 38, 135, 141 suppression, 110, 112 suppressor, 85, 97, 102, 114 Surgeons, 6 surgery, 6, 33, 38 Surgery, 28, 49, 50, 51, 52, 53, 54, 55, 264 surgical, 7, 28, 51 surplus, 139, 143 surprise, 77, 99, 199 surrogates, 25 surveillance, 11, 84, 273, 275, 281 Survey, 179, 181, 198, 213, 216, 221, 236, 238 survival, 7, 12, 85, 128, 159, 285, 286, 287, 289, 297, 299 survivors, 4, 84, 85, 285, 299 susceptibility, 108, 118, 119, 120, 124, 125, 138, 244, 248, 275, 280, 281, 285, 287, 292, 297 swallowing, 92 Sweden, 148, 235, 280 switching, 140 Switzerland, 28, 50, 70, 108 symbiosis, 101 symbolic, ix, 144, 153 sympathy, 174 symptom, 131 symptoms, vii, 20, 35, 36, 51, 57, 71, 155, 286, 287 synapse, 92, 112, 120, 121, 122, 126 synapses, 126 syncytium, 250 syndrome, vii, ix, 29, 39, 40, 84, 127, 130, 245, 250, 256, 258, 266, 275, 293, 294 synergistic, 98 synergistic effect, 98 Synergy, 296 synthesis, 20, 256, 258, 305 synthetic, 262, 263 systemic circulation, 89 systems, 134, 137, 142, 144, 156, 157, 261

341

T T cell, v, viii, x, xi, 41, 82, 85, 87, 88, 89, 90, 91, 92, 93, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 128, 243, 245, 251, 254, 255, 266, 267, 271, 272, 274, 276, 278, 281, 284, 285, 288, 289, 296, 297, 301 T cells, v, viii, x, xi, 41, 82, 88, 89, 90, 91, 92, 93, 95, 96, 97, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 117, 118, 119, 120, 121, 122, 124, 126, 127, 128, 254, 255, 271, 272, 274, 276, 278, 281, 284, 285, 288, 289, 296, 297, 301 T lymphocyte, 11, 12, 103, 104, 112, 125, 268, 284, 285, 295, 296, 307 T regulatory cells, 93, 289 Tanzania, 133, 140, 141, 149, 150, 228, 237, 248 target population, 25 target populations, 25 targets, 19, 29, 71, 90, 113, 267, 276, 294, 301 taxes, 144 T-cell receptor, 119, 125 T-cells, 21, 41, 122, 255, 265 teachers, 9, 27, 28, 212 technological, 29, 45 technological developments, 29 technology, 16, 18, 24, 25, 30, 32, 122, 283 teenagers, 238 telephone, 42 television, 164, 208 temporal, 133 tension, 195 territory, 301 tertiary, 161, 222 tertiary education, 161 testes, 10 tetanus, 2, 12 Thailand, 22, 92 T-helper cell, 19 theoretical, 50 theory, 141, 151, 155, 283, 290 therapeutic, v, vii, x, 1, 7, 17, 18, 23, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 43, 44, 45, 47, 67, 68, 86, 117, 118, 128, 241, 261, 272, 284, 290 therapy, 7, 31, 36, 38, 39, 40, 41, 43, 44, 51, 57, 61, 62, 88, 122, 123, 127, 242, 248, 253, 255, 256, 258, 261, 264, 265, 267, 268, 269, 276, 284, 293, 297 thinking, 12, 16, 19, 34, 41, 190, 203, 206

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342

Index

third party, 100 Third World, 64, 146 Thomson, 156, 237 threat, 15, 27, 139, 210 threatened, 207, 209, 210, 211 threatening, 7, 207 threshold, 282 thrombin, 269 thrombocytopenia, 260, 265, 268 thromboxane, 259 thrombus, 259 thrush, 36 thymus, 268 time, 2, 3, 5, 6, 7, 8, 9, 12, 13, 14, 16, 18, 19, 20, 21, 24, 27, 29, 32, 34, 35, 36, 40, 41, 44, 45, 55, 57, 58, 64, 66, 67, 70, 78, 80, 81, 92, 94, 96, 99, 101, 132, 137, 139, 141, 154, 157, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 171, 172, 174, 176, 177, 180, 181, 182, 183, 184, 186, 190, 194, 196, 197, 200, 201, 202, 210, 211, 212, 214, 215, 216, 217, 218, 219, 225, 234, 237, 256, 257, 263, 277, 282, 283, 289, 302, 306 time frame, 2, 92, 234 timing, 172, 286 tissue, x, 8, 9, 10, 11, 21, 92, 94, 97, 118, 244, 262, 271, 275, 278, 284, 304, 308, 310 title, 19 T-lymphocytes, 19, 21, 29, 42 tobacco, 170, 220, 225, 227, 229, 231 tocopherols, 268 tocotrienols, 269 Togo, 133 Tokyo, 117 tolerance, 94, 105, 115, 261 Toll-like, 107 top management, 53 total cholesterol, 257 toxic, 14, 29, 51, 122, 248, 251, 291 toxic effect, 251 toxicity, 35, 38, 43, 273 toxin, 94, 95, 96 trace elements, 244 trade, 133, 136, 137, 139, 142, 144, 223 trade liberalization, 136, 137 trade-off, 139 trading, 143 traditional, 154, 200, 211 Traditional, 154, 223 traditional practices, 154 traditions, 154

traffic, 301 training, 5, 21, 27, 28, 30, 32, 50, 52, 53, 57, 74, 159 traits, 277 trajectory, 309 trans, 106, 120, 124, 126, 127, 131 transcriptase, 255, 256, 258, 266 transcription, x, 20, 89, 120, 241, 245, 250, 254, 255, 258, 267, 279, 305, 307 transcription factor, x, 241, 245, 250, 254, 255, 305 transcriptional, 305, 309 transcripts, 83, 273, 274, 283, 294 transduction, 122, 125, 257, 309 transfer, 120, 121, 122, 124, 126, 127, 251, 267 transformation, 278 transfusion, 32, 33, 38, 74 transfusions, 33 transition, 154 translation, 83 Translation, 235 translocation, 96, 119, 249, 257, 305 transmembrane, 277, 301 transmission, vii, viii, 26, 28, 29, 41, 42, 85, 87, 88, 89, 90, 91, 92, 94, 96, 98, 100, 102, 103, 106, 108, 110, 111, 112, 113, 114, 118, 120, 121, 122, 126, 127, 134, 136, 137, 139, 141, 144, 155, 212, 217, 236, 237, 265, 294 transmits, 104 transnational, 144 transplant, x, xi, 271, 272, 273, 274, 283, 284, 285, 286, 288, 289, 290, 292, 294, 295, 297, 299 transplant recipients, 285, 286, 288, 289, 295 transplantation, v, x, 271, 272, 273, 274, 278, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 294, 296, 299 transport, 127, 256, 259, 263, 269 transportation, 42 travel, 137, 143, 301 treatable, 36 trend, 158, 246, 253 trial, 2, 10, 26, 35, 36, 68, 82, 86, 235, 248, 249, 253, 265 trigeminal, 309 triggers, 80 triglycerides, 257 tropism, 105 truism, 45 trust, 134, 166, 167, 175, 215, 217, 219 Tsonga, 159 tuberculosis, 14, 120 tumor, 123, 264, 273

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,

Index tumor necrosis factor, 123, 264, 273 tumors, vii, 245 tumour, 11 turnover, 126, 140, 295, 301

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U Uganda, 22, 132, 133, 135, 142, 150 ulcer, 91, 113 ultrastructure, 255 ultraviolet light, 2, 8 undergraduate, 27, 53 undifferentiated, 306 unemployment, 158, 211 uniformity, 30 United Nations, vii, 1, 3, 14, 15, 21, 46, 47, 51, 63, 64, 65, 68, 69, 70, 137, 150 United Nations Development Program UNDP, 136, 138, 141, 150 United States (US), ix, 7, 13, 14, 43, 45, 50, 56, 69, 72, 83, 91, 129, 134, 156 univariate, 286 universities, 15 urban, 135, 142, 155, 158, 159, 223, 224, 225, 234, 237 urban areas, 159 Urbanisation, 236 urbanization, 140, 158, 211, 225 urea, 2, 60 uric acid, 41 urinary, 109, 244, 265 urinary tract, 244 urinary tract infection, 244 US dollar, 141 US, see United States, 156 users, 6 USSR, 9, 10 uveitis, 40

V vaccination, v, viii, 4, 6, 9, 10, 25, 62, 82, 88, 89, 90, 94, 98, 101, 104, 107, 109, 110, 117, 122 vaccinations, 10, 36 vaccine, vii, viii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 51, 57, 62, 63, 64, 65, 68, 70, 71, 73, 74, 75, 76, 77, 79, 81, 82, 83, 84, 85,

343

86, 87, 88, 89, 90, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, 108, 109, 110, 111, 112, 113, 115, 117, 118, 122, 123 vaccines, iv, vii, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 35, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 59, 62, 63, 64, 65, 66, 69, 70, 71, 73, 74, 75, 76, 77, 79, 82, 83, 88, 89, 90, 94, 95, 100, 102, 103, 106, 107, 108, 110, 111, 113, 118, 126 vagina, 91, 92, 111, 160, 194, 196, 197, 200, 210 vaginal, vii, 36, 41, 94, 95, 97, 98, 100, 104, 105, 108, 109, 120, 141, 196 validity, 69, 160 values, 154, 156, 185, 274, 282 variability, 39, 299 variable, 79, 119 variables, 136, 156, 208, 219, 233, 283, 288 Variables, 208, 219, 233 variation, 19, 84, 99, 285, 297 vascular, 243, 276 vascular cell adhesion molecule, 243 vascularization, 310 vector, 89, 119, 122, 125, 130, 158 vehicles, 50 ventricle, 305 ventricular, 301 Vermont, 7, 129 vertebrates, xi, 300, 304, 305, 307, 308 vesicle, 303, 304 Vice President, 73, 74 victims, 7, 8 Victoria, 66, 138, 139, 147 video, 59 village, 50 violence, 143, 158, 160, 182, 209, 211, 225, 227, 230, 231, 236, 237 violent, 137, 139 viral, viii, x, xi, 7, 8, 17, 18, 19, 20, 21, 22, 24, 26, 29, 30, 31, 32, 41, 43, 62, 84, 85, 87, 88, 89, 90, 91, 93, 94, 96, 98, 99, 100, 101, 103, 109, 113, 114, 115, 119, 122, 123, 126, 127, 134, 143, 144, 241, 244, 245, 246, 248, 251, 254, 255, 256, 259, 264, 272, 273, 275, 278, 279, 280, 282, 283, 290, 292, 294, 297 viral diseases, 32 viral envelope, 18, 19, 20, 31 viral infection, xi, 7, 24, 29, 88, 90, 91, 101, 103, 122, 272, 273, 278, 279, 280 viral vectors, 89 virological, 92, 112

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Index

344

virology, 17, 30, 32 virus, vii, viii, ix, xi, 1, 2, 3, 6, 7, 8, 9, 10, 13, 16, 17, 18, 19, 20, 21, 28, 29, 33, 36, 37, 39, 43, 55, 62, 79, 82, 83, 86, 87, 89, 90, 91, 92, 95, 97, 98, 99, 101, 102, 103, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 130, 131, 132, 134, 137, 141, 147, 242, 250, 255, 256, 264, 266, 267, 269, 273, 278, 282, 297, 298, 300 virus infection, 104, 105, 107, 109, 113, 297, 298 virus replication, 90, 110, 114, 120, 122, 256, 266 viruses, 2, 5, 6, 13, 17, 29, 43, 44, 83, 91, 92, 94, 97, 99, 100, 102, 118, 123, 125, 245, 257, 273, 283, 291, 293 visa, 19, 50 vitamin A, 243, 248 vitamin C, 243, 244, 248, 253, 256, 257, 265, 266, 267 Vitamin C, 253 vitamin D, 298 vitamin D receptor, 298 vitamin E, x, 241, 243, 244, 245, 246, 248, 249, 250, 251, 253, 255, 256, 257, 259, 260, 261, 262, 263, 264, 266, 267, 268, 269 vitamin supplementation, 243 vitamins, x, 241, 243, 244, 245, 251, 253, 261, 264, 266, 267 vocational, 159, 233 vocational training, 159 vomiting, 201, 243 vulnerability, ix, 132, 134, 136, 141, 150, 153, 157

western blot, 105 Western-style, 134 White, 213, 221 white blood cells, 36 wild type, 277, 287, 288 windows, 8 Wisconsin, 146 wisdom, 57 witness, viii, 87 wives, 134 Wnt signaling, 305 women, 26, 41, 79, 85, 88, 97, 98, 100, 113, 114, 132, 134, 135, 138, 139, 140, 141, 144, 150, 157, 158, 180, 182, 189, 190, 191, 207, 208, 225, 234, 236, 237, 248 Women, 157, 190, 235 work, 156, 158, 165, 166, 171, 175, 188, 202, 205, 237, 244 workers, 41, 82, 100, 107, 135, 137, 139, 140, 142, 158 working class, 225 World Bank, 136, 137, 140, 141, 146, 150, 151 World Health Organization (WHO), ix, 5, 13, 14, 15, 17, 26, 28, 50, 51, 56, 64, 69, 70, 84, 88, 115, 129, 138, 141, 146, 150, 155, 239 worry, 28, 182, 183, 217 writing, 3, 38, 39

X xenobiotic, 261, 269 xenobiotics, 261

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W walking, 200 war, 3, 133, 137 warts, 4 Washington, 22, 150, 266 waste, 194 water, 8, 10, 14, 15, 45, 76, 137, 138, 253 water-soluble, 253 wealth, 4, 14, 140, 141 wear, 141 weight gain, 56 wellbeing, 135 well-being, 36, 56 well-being, 154 well-being, 157 West Africa, 19, 52, 100, 133, 135 West Nile virus, 298

Y yellow fever, 2, 12, 42, 62 yolk, 304 young adults, 3, 188 young men, 157 young women, 157, 159, 207, 225

Z zebrafish, xi, 300, 302, 303, 305, 307, 308, 309, 310, 311 Zimbabwe, 13, 133, 137, 140, 141, 142, 145, 146, 148, 149, 150 Zinc, 267

AIDS Vaccines, HIV Receptors, and AIDS Research, edited by Lawrence B. Kendow, Nova Science Publishers, Incorporated, 2008. ProQuest Ebook Central,