How many human immune systems are there? How old are they? Why is there no AIDS vaccine? Is a new approach needed? Why is public opinion growing skeptical of the scientific community after three decades of public awareness about HIV/AIDS? Consider answers to these puzzling questions. Learn from the decades of experience of two senior scholars: Dr. Omar Bagasra (an eminent molecular biologist, immunologist, and retrovirologist) and Dr. Donald Gene Pace (a highly published writer who examines public health policy). Explore intriguing new possibilities about human immunity, and the development of an effective AIDS vaccine. Read Immunology and the Quest for an HIV Vaccine. Benefit from an informed synthesis backed by a wealth of peer-reviewed scientific references. Review basic concepts of immunology, and stretch your perspective by contemplating this creative synthesis that provides a provocative treatise on the origin, evolution, and etiology of several forms of immune systems. Consider compelling ideas that will have an important bearing on HIV vaccine development. Enjoy this informative volume designed for anyone interested in the development of a safe AIDS vaccine, for anyone curious about present knowledge about human immunity, and for anyone yearning for a solution to the global pandemic that is AIDS.

Immunology and the Quest for an HIV Vaccine

A New PerspectiveBy Omar Bagasra Donald Gene Pace

AuthorHouse

Copyright © 2012 Dr. Omar Bagasra, MD, PhD and Dr. Donald Gene Pace, PhD.
All right reserved.
ISBN: 978-1-4685-0830-7

Contents

PREFACE..............................................................................................ixACKNOWLEDGMENTS......................................................................................xvLIST OF FIGURES AND TABLES...........................................................................xviiCHAPTER 1 A SHIFT IN THE CURRENT CONCEPT OF HIV VACCINE..............................................1Evolution of Intracellular Molecular Defense.........................................................3Protective Role of Endogenous Retroviruses in Sheep..................................................5Evolution of Classical Immunity......................................................................8Why Move Beyond Classical Immunity?..................................................................11Broadly Neutralizing Antibodies: Development of Antibodies against HIV-1.............................12Do Neutralizing Antibodies Protect African Non-human Primates?.......................................14The Problem..........................................................................................17Examples of Long-term Nonprogressors (LTNPs), Elite Suppressors (ES).................................19Exposed-but-Resistant: Kenyan Sex Workers Appear Immune to HIV Infection.............................19Future Direction of miRNA Research: miRNA Delivery...................................................20A Strange Case of HIV Cure...........................................................................35CHAPTER 2 IMMUNITY: OLD PARADIGM VERSUS NEW..........................................................41The Foundation of Molecular Immunity.................................................................45Inadequate Current Paradigm: Nature, Origin, and Functions of Classical Immunity.....................48The HLA Genetic Determinants Are Not the Only Protective Mechanism...................................52Molecular Immunity Arrived from Transposons and Retroelements........................................54Recent Evidence Related to Origins of RNAi and miRNA Silencing Systems...............................55Endogenous Retroviruses: Protective Lessons..........................................................59Innate Immunity and Immune Defense Based on Pattern Recognition......................................61Evolution of Anti-transposon Resistance in Bacteria to Large Mammals.................................63Perspective from Fungal Molecular Defense............................................................64Immunity's Big Bang..................................................................................72Summary..............................................................................................79CHAPTER 3 THE ARCHITECTURE OF THE CLASSICAL IMMUNE SYSTEM............................................81The Innate Immune System.............................................................................82The Classic, or Adaptive, Immune System..............................................................86EPILOGUE.............................................................................................107REFERENCES...........................................................................................111BIBLIOGRAPHY.........................................................................................135

Chapter One

A SHIFT IN THE CURRENT CONCEPT OF HIV VACCINE

"The cellular immune response (via cytotoxic T lymphocytes, or CTLs) plays a significant role in modulating the level of infected cells but is incapable of clearing them altogether for a couple of reasons. For one, as the number of infected cells declines, the number of CTLs also declines. For another, HIV replication targets the CD4+ T helper cells – the very cells that are essential for the most effective CTL killing. This leaves only a relatively weak helper cell-independent response. The upshot is that even when antiviral therapy has reduced the number of productively infected cells by as much as 6 orders of magnitude, the immune system cannot clear the small residue of infected cells. If therapy is discontinued, even after many years of treatment, the infection always recovers to previous levels."

John Coffin, "Searching For Achilles' Heel." Microbe 2009; 4 (5), 224. Thomas S. Kuhn's Structure of Scientific Revolutions shows that paradigms shift when diverse aggregated evidence invites revision. Recent decades have witnessed the failure to formulate a classical immunity-based anti-HIV vaccine. We argue that resistance against an invading retrovirus such as HIV-1 is based on intracellular immunity that evolved in the form of small dsRNA (e.g., miRNA, RNAi, etc.). Lentiviruses (LVs), specifically SIVs, endemically infect over 40 different African non-human primates (reviewed in 2-6), and provide useful models for HIV-1 molecular studies. Although natural hosts to SIVs, African non-human primates typically do not develop immunodeficiency or AIDS, although they exhibit high degrees of viremia. It should be noted that the high degree of viremia does not kill the African nonhuman primates, including chimpanzees that harbor almost the same virus as HIV-1, or make them very immunodeficient. And, more pointedly, why is our criteria for treating HI-infected individuals with highly active anti-retroviral therapy (called HAART) mainly based on measuring the viral load and CD4+ T cell count? More, importantly, only certain Asian macaques generally exhibit viremia and progressive loss of CD+ Tlymphocytes. Why differences in pathogenicity exist has been subject of much speculation, and no conventional immunological approach has deciphered which viral and/or host factors account for African nonhuman primates resistance. We hypothesize that African non-human primates find protection through selective and differential expressions of SIV homologous microRNA (miRNA) that form stable complexes with the virus. We also believe that a similar protective mechanism is operational in a small group of infected humans resistant to HIV-1 and others that experience long-term latency. Although retroelements have infected life forms that predate classical immunity's evolution (4 billion versus 350 million years), these intracellular invaders are checked by intracellular small double-stranded nucleic acid-based defense mechanisms (i.e., miRNAs and/or non-coding ncRNAs). We will describe various aspects of this immunity throughout this book.

Evolution of Intracellular Molecular Defense

Many believe early life on earth was RNA in nature, as were primitive parasitic life forms (i.e., retroelements) that invaded them. RNA molecules performed enzymatic functions as ribozymes, and bioinformation storage functions as genomes. Early RNAs were invaded by primitive retroelements – retrotransposons – whose ribozymes served as polymerase for self-replication. As evolution moved forward, RNA evolved into more stable DNA genomic storage molecules, and proteins assumed complex enzymatic roles when multiple structural molecules evolved. RNA branched-off into specialized molecules serving as biodefense network and gene regulator. Current research clearly supports the notion that the majority of the human intracellular defenses derived from...