Human Retroviral Infections. Immunological and Therapeutic Control

Transcription

1 Human Retroviral Infections Immunological and Therapeutic Control

2 INFECTIOUS AGENTS AND PATHOGENESIS Series Editors: Mauro Bendinelli, University of Pisa Herman Friedman, University of South Florida College of Medicine Recent volumes in this series: DNA TUMOR VIRUSES Oncogenic Mechanisms Edited by Guiseppe Barbanti-Brodano, Mauro Bendinelli, and Herman Friedman ENTERIC INFECTIONS AND IMMUNITY Edited by Lois J. Paradise, Mauro Bendinelli, and Herman Friedman FUNGAL INFECTIONS AND IMMUNE RESPONSES Edited by Juneann W. Murphy, Herman Friedman, and Mauro Bendinelli HERPESVIRUSES AND IMMUNITY Edited by Peter G. Medveczky, Herman Friedman, and Mauro Bendinelli HUMAN RETROVIRAL INFECTIONS Immunological and Therapeutic Control Edited by Kenneth E. Ugen, Mauro Bendinelli, and Herman Friedman MICROORGANISMS AND AUTOIMMUNE DISEASES Edited by Herman Friedman, Noel R. Rose, and Mauro Bendinelli OPPORTUNISTIC INTRACELLULAR BACTERIA AND IMMUNITY Edited by Lois J. Paradise, Herman Friedman, and Mauro Bendinelli PSEUDOMONAS AERUGINOSA AS AN OPPORTUNISTIC PATHOGEN Edited by Mario Campa, Mauro Bendinelli, and Herman Friedman PULMONARY INFECTIONS AND IMMUNITY Edited by Herman Chmel, Mauro Bendinelli, and Herman Friedman RAPID DETECTION OF INFECTIOUS AGENTS Edited by Steven Specter, Mauro Bendinelli, and Herman Friedman RICKETTSIAL INFECTION AND IMMUNITY Edited by Burt Anderson, Herman Friedman, and Mauro Bendinelli A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

3 Human Retroviral Infections Immunological and Therapeutic Control Edited by Kenneth E. Ugen University of South Florida College of Medicine Tampa, Florida Mauro Bendinelli University of Pisa Pisa, Italy and Herman Friedman University of South Florida College of Medicine Tampa, Florida Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow

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5 Contributors MICHAEL G. AGADJANYAN Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and Institute of Viral Preparations, Russian Academy of Medical Science, Moscow, Russia J. ARP Gene Therapy and Molecular Virology Group, The John P. Robarts Research Institute, and the Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5K8 VELPANDI AYYAVOO Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania MOSI K. BENNETT Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania EWA BJÖRLING Microbiology and Tumorbiology Center, Karolinska Institute, S Stockholm, Sweden JEAN D. BOYER Stellar-Chance Laboratories, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania CYNTHIA L. BRISTOW McLendon Clinical Laboratories, Department of Pathology and Laboratory Medicine, University of North Carolina Hospitals, Chapel Hill, North Carolina GEORGE J. CIANCIOLO Department of Pathology, Duke University Medical Center, Durham, North Carolina JOSEPH P. COTROPIA BioClonetics, Inc., Philadelphia, Pennsylvania 19147, and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania v

6 vi CONTRIBUTORS G. A. DEKABAN Gene Therapy and Molecular Virology Group, The John P. Robarts Research Institute, and the Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5K8 MAITE DE LA MORENA Washington University School of Medicine, St. Louis, Missouri ROBERT W. DOMS Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania BENJAMIN J. DORANZ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania RALPH DORNBURG The Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania PATRICIA J. EMMANUEL Department of Pediatrics, College of Medicine, University of South Florida, Tampa, Florida G. FRANCHINI Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland TERESA C. GENTILE Department of Medicine, SUNY Health Sciences Center, Syracuse, New York MAUREEN M. GOODENOW Department of Pathology, Immunology, and Laboratory Medicine, and Division of Immunology and Infectious Diseases, Department of Pediatrics, College of Medicine, Health Science Center, University of Florida, Gainesville, Florida THOMAS KIEBER-EMMONS Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania SAGAR KUDCHODKAR Stellar-Chance Laboratories, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania THOMAS P. LOUGHRAN Program Leader, Hematological Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Veterans Administration Hospital, and Departments of Medicine and Microbiology/Immunology, University of South Florida College of Medicine, Tampa, Florida JERRY R. McGHEE Department of Microbiology, Immunobiology Vac-

7 CONTRIBUTORS vii cine Center, University of Alabama at Birmingham, Birmingham, Alabama T. NAGASHUNMUGAM Stellar-Chance Laboratories, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ROBERT P. NELSON, JR. Indiana University School of Medicine, Indianapolis, Indiana ELENA E. PEREZ Department of Pathology, Immunology, and Laboratory Medicine, and Medical Scientist Training Program, College of Medicine, Health Science Center, University of Florida, Gainesville, Florida A. PETERS Gene Therapy and Molecular Virology Group, The John P. Robarts Research Institute, and the Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5K8 ROGER POMERANTZ The Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania AMI R. SHAH Rollins School of Public Health, Emory University, Atlanta, Georgia JOHN W. SLEASMAN Department of Pathology, Immunology, and Laboratory Medicine, and Division of Immunology and Infectious Diseaes, Department of Pediatrics, College of Medicine, Health Science Center, University of Florida, Gainesville, Florida HERMAN F. STAATS Departments of Medicine and Immunology, Center for AIDS Research, Duke University Medical Center, Durham, North Carolina KENNETH E. UGEN Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, Florida DAVID B. WEINER Stellar-Chance Laboratories, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

8 Preface to the Series The mechanisms of disease production by infectious agents are presently the focus of an unprecedented flowering of studies. The field has undoubtedly received impetus from the considerable advances recently made in the understanding of the structure, biochemistry, and biology of viruses, bacteria, fungi, and other parasites. Another contributing factor is our improved knowledge of immune responses and other adaptive or constitutive mechanisms by which hosts react to infection. Furthermore, recombinant DNA technology, monoclonal antibodies, and other, newer methodologies have provided the technical tools for examining questions previously considered too complex to be successfully tackled. The most important incentive of all is probably the regenerated idea that infection might be the initiating event in many clinical entities presently classified as idiopathic or of uncertain origin. Infectious pathogenesis research holds great promise. As more information is uncovered, it is becoming increasingly apparent that our present knowledge of the pathogenic potential of infectious agents is often limited to the most noticeable effects, which sometimes represent only the tip of the iceberg. For example, it is now well appreciated that pathologic processes caused by infectious agents may emerge clinically after an incubation of decades and may result from genetic, immunologic, and other indirect routes more than from the infecting agent in itself. Thus, there is a general expectation that continued investigation will lead to the isolation of new agents of infection, the identification of hitherto unsuspected etiologic correlations, and, eventually, more effective approaches to prevention and therapy. Studies on the mechanisms of disease caused by infectious agents demand a breadth of understanding across many specialized areas, as well as ix

9 x PREFACE TO THE SERIES much cooperation between clinicians and experimentalists. The series Infectious Agents and Pathogenesis is intended not only to document the state of the art in this fascinating and challenging field, but also to help lay bridges among diverse areas and people. M. Bendinelli H. Friedman

10 Preface The discovery of the human T cell leukemia virus type I in the late 1970s heralded a new era in retrovirology. For the first time, it was demonstrated that a retrovirus could play a role in the development of a human disease, in this case adult T cell leukemia (ATL). Several years later, the acquired immunodeficiency syndrome (AIDS) epidemic began, and it was demonstrated that a retrovirus, originally designated the human T cell lymphotropic virus type 3, was the causal agent of this syndrome. This virus, later named the human immunodeficiency virus type 1 (HIV-1), has since been extensively studied in terms of its pathogenesis as well as its ability to elicit immune responses. In that time, a tremendous amount of information has been obtained about the virus. Although recent drug regimens have been useful in significantly lowering viral loads and perhaps maintaining an asymptomatic state among individuals infected with HIV-1, an established cure for AIDS eludes us. In addition, the effective drug therapies are very expensive, and are not available to infected people in the third world, where greater than 90% of new infections occur. Furthermore, the development of viral resistance against the drug therapies is an additional concern. Despite extensive study, no effective vaccine has been developed. One of the problems in developing an effective vaccine against HIV-1 is the ability of the virus, particularly in the immunogenic envelop glycoprotein, to undergo amino acid hypervariability. Therefore, vaccines generated against one envelop glycoprotein are ineffective against other viruses with more hypervariable envelopes. Although the rate of new HIV-1 infections in the United States has slowed and appears to have reached a plateau, nearly 16,000 people per day worldwide become newly infected with this devastating virus. Ominously, it is predicted that at the turn of the century, over 40 million people across the globe will be infected. Clearly, the development of new effective drug therapies, as well as immune prophylactic and therapeutic regimens against xi

11 xii PREFACE HIV and AIDS is warranted. The chapters in this volume, written by experts in the field of human retroviral pathogenesis, vaccine development, and the clinical treatment of AIDS, summarize the current status of work in these areas as well as future directions for research and therapeutic development. The first chapter, by Dr. Bristow, deals with the important descriptions of the two principal viremias of HIV-1, sexual (heterologous) transmission and autologous transmission of viruses between cells within the same host. This information is relevant for the development of methods to limit the spread of HIV-1 infection. Drs. Gentile and Loughran then describe evidence for the role of the human T cell leukemia viruses (HTLV) in the etiology and pathogenesis of disorders other than ATL. This is an interesting and important area because of evidence suggesting that the HTLVs may have a role in a number of autoimmune diseases. Next, Dr. Cianciolo discusses the evidence for the immunomodulatory and immunosuppressive activity for a number of HIV-1 proteins including gp120 and gp41 as well as the regulatory proteins Tat and Nef. Dr. Kieber-Emmons describes the importance of carbohydrate moieties and glycosylation patterns in HIV-1 and their role in masking potentially immunogenic and therapeutically important epitopes. Drs. Bennett and Agadjanyan summarize some of the immunologic and molecular aspects of HTLV-I and HTLV-II infection, emphasizing the role of adhesion molecules in the binding of these two viruses to infectible target cells. The next set of chapters deals with issues concerning the development of immunologic interventions against HTLV, HIV-2, and HIV-1, including vaccine development and passive immunotherapies. Dr. Franchini and colleagues describe the current status of efforts to develop a vaccine against HTLV-I, a retrovirus that infects million people worldwide. Dr. Björling discusses immune responses against HIV-2 and how these responses are important for the development of vaccine strategies against this retrovirus, which primarily infects individuals in West Africa. Drs. Staats and McGhee deal with the important need to develop vaccine strategies against HIV-1 which will protect against mucosal infection. Since HIV-1 is transmitted primarily by mucosal routes, this is a very timely and important issue in the area of HIV-1 vaccinology. In terms of novel vaccine strategies against HIV-1, Dr. Boyer and colleagues describe the nucleic acid (DNA) vaccination technology. This approach, which appears to mimic live, attenuated viral vaccines without major safety concerns, elicits both humoral and cytotoxic T cell responses against HIV-1, and is currently in several human clinical trials. Drs. Cotropia and Ugen describe the current status of passive immunotherapy and immunoprophylaxis against HIV-1, including the use of human polyclonal HIV immunoglobulins and specific neutralizing human monoclonal antibodies. The set of chapters dealing with immunologic interven-

12 PREFACE xiii tions ends with the description by Dr. Ayyavoo and colleagues of efforts to target the accessory genes of HIV-1 for vaccine development and immunotherapy. The final set of chapters deals with developments in therapeutic interventions against HIV-1 infection and AIDS using drugs or gene therapy. Drs. Doranz and Doms discuss the role of chemokine receptors in mediating entry of HIV-1 into cells as well as the design of new antiviral therapeutics that may prevent HIV from using these receptors. Dr. Goodenow and colleagues then summarize the activities of the therapeutically important protease inhibitors and, in particular, describe the role of genetic variability of the HIV-1 protease in modulating the response to these drugs in pediatric patients. Drs. Dornburg and Pomerantz follow with a chapter that describes current ideas and implementations of gene therapeutic regimens against HIV-1, as well as future possibilities of such an approach. The volume concludes with a chapter by Dr. Nelson and colleagues on the current status of the clinical use of antiretroviral therapy against pediatric HIV, the relative effectiveness of this therapy, and the need for the development of new therapies. It is anticipated by the editors as well as by the authors of the individual chapters that this volume will provide a useful summary of the current status of immunologic and therapeutic interventions against human retroviral infections, most notably HIV-1. It is hoped that the need is made apparent for the development of efficacious vaccines against both HIV-1 and HTLV-I, as well as for the development of novel drug therapies and regimens such as gene therapy against HIV-1. The editors thank Ilona Friedman for excellent editorial assistance in coordinating and assisting in the preparation of the manuscripts for this volume. Kenneth E. Ugen Mauro Bendinelli Herman Friedman

13 Contents 1. The Two Principal Viremias of HIV: A Comparison of Viral and Host Characteristics CYNTHIA L. BRISTOW 1. Introduction Sexual Transmission The Infectious Unit The Target Cell The Environment Autologous Transmission The Infectious Unit The Target Cell The Environment Conclusions References Potential Role of Human T-cell Leukemia/Lymphoma Viruses (HTLV) in Diseases Other Than Acute T-cell Leukemia/ Lymphoma (ATL) TERESA C. GENTILE and THOMAS P. LOUGHRAN 1. Introduction Neurologic Disease Hematologic Disease Autoimmune/Inflammatory Dermatologic Disease xv

14 xvi CONTENTS 6. Other Reported Disease Associations References Viral-Related Proteins in Immune Dysfunction Associated with AIDS GEORGE J. CIANCIOLO 1. Immunologic Dysfunction Associated with HIV Infection Reported Effects of HIV-1 Tat on Immune Cell Function Reported Effects of HIV-1 gp120 on Immune Cell Function Reported Effects of HIV-1 gp41 on Immune Cell Function Reported Effects of HIV-1 Nef on Immune Cell Function Summary References Carbohydrate Interactions and HIV THOMAS KIEBER-EMMONS 1. Introduction Carbohydrate Structures Are Ubiquitous in Nature Influence of Carbohydrate Moieties on the Immunogenicity of HlV Role of Carbohydrate in Vaccine Strategies to HIV Mucosal Immune Responses Summary References HTLV-I and HTLV- II Infection: Immunological and Molecular Aspects MOSI K. BENNETT and MICHAEL G. AGADJANYAN 1. Introduction Biology of HTLV HTLV Vaccine Development Receptors for HTLV Adhesion Molecules and HTLV Infection References

15 CONTENTS xvii 6. Vaccine Approaches for Human T-cell Lymphotropic Virus Type I G. A. DEKABAN. A. PETERS. J. ARP. and G. FRANCHINI 1 Introduction Issues Relevant to HTLV-I Vaccine Development HTLV-I Tropism The Natural Immune Response to HTLV-I Infection Feasibility of Generating an HTLV-I Vaccine Genetic Stability Available Animal Models Rodent Models Nonhuman Primate Models Modes of Challenge Vaccine Approaches Relevant to HTLV-I Inactivated and Live Attenuated Viruses Subunit Approach Live Vectors Immunization by DNA Gene Transfer HTLV-I Vaccine Candidates Tax Pol and px Region Proteins Envelope Glycoprotein Gag Polyvalent Vaccine HTLV-I Animal Vaccine Challenge Studies Rat Vaccine Studies Rabbit Vaccine Studies Nonhuman Primate Vaccine Studies Summary References Immune Responses against HIV EWA BJÖRLING 1. Introduction Properties of Different HIV-2 Proteins Immune Responses against HlV Humoral Immunity Antibody-Dependent Cellular Cytotoxicity

16 xviii CONTENTS 3.3. Cell-Mediated Immunity Conclusion References HIV Mucosal Vaccines HERMAN F. STAATS and JERRY R. McGHEE 1. Introduction HIV Infection at Mucosal Surfaces Correlates of Protection for Mucosally Transmitted HIV HIV-Exposed but Uninfected Mucosal SIV Challenge in Nonhuman Primates Mucosal HIV Vaccine Needed Organization of the Mucosal Immune System Mucosal Antibody Responses: Secretory-IgA Mucosal Cell-Mediated Immunity: Cytotoxic T Lymphocytes Routes of Immunization for the Induction of Anti-HIV Mucosal Immune Responses Mucosal HIV Vaccine Strategies Protein Subunits Peptide Vaccines Virus-like Particles Recombinant Viral Vectors Recombinant Bacterial Vectors DNA Vaccines Live Attenuated SlV Mucosal Adjuvants Conclusions References Nucleic Acid Vaccination against HIV AMI R. SHAH, DAVID B. WEINER, and JEAN D. BOYER 1. Introduction Obstacles to HIV-1 Vaccine Development Introduction Immune Responses to HIV-1 and Potential Correlates of Protection

17 CONTENTS xix 3. The Genome of HIV-1 and Targets for Nucleic Acid Vaccination DNA-Based Vaccines Progress of Nucleic Acid Immunization against HIV Murine Studies Primate Studies Human Studies Conclusion References Passive Immunotherapy against HIV-1: Current Status and Potential JOSEPH P. COTROPIA and KENNETH E. UGEN 1. Introduction Humoral Immune Responses against HIV Humoral Immune Responses against gp Humoral Immune Responses against gp Convergent/Synergistic Passive Immunotherapy Evidence for Protective Efficacy of Humoral Immunity against HIV Passive Immunotherapy Trials of Clinical Relevance Utilizing HIV Immune Serum Globulin Monoclonal Antibodies Utilized in Passive Immunotherapy Chimpanzee Model Human Trials hu-pbl-scid Mouse Model Summary References Human Immunodeficiency Virus Type 1 Accessory Genes: Targets for Therapy SAGAR KUDCHODKAR, T. NAGASHUNMUGAM, and VELPANDI AYYAVOO 1. Introduction Vif Structure and Function Vaccine and Drug Studies

18 xx CONTENTS 3. Vpu Structure and Function Vaccine and Drug Studies Nef Structure and Function Vaccine and Drug Studies Vpr Structure and Function Vaccine and Drug Studies Conclusion References A New Generation of Antiviral Therapeutics Designed to Prevent the Use of Chemokine Receptors for Entry by HIV-1... BENJAMIN J. DORANZ and ROBERT W. DOMS Introduction Chemokine Receptors as HIV-1 Coreceptors Chemokine Receptors as Pathogenic Determinants Chemokine Inhibition of HIV Therapeutics Directed at Chemokine Receptors Small-Molecule Inhibitors of Chemokine Receptors Future Directions References Protease Inhibitors and HIV-1 Genetic Variability in Infected Children MAUREEN M. GOODENOW, ELENA E. PEREZ, and JOHN W. SLEASMAN 1. Antiviral Drug Therapies Introduction HIV-1 Targets for Drugs HIV-1 Protease Viral Drug Resistance Antiviral Drugs and Pediatric Patients Drugs for HIV-1-Infected Children Protease Inhibitors and Clinical Response

19 CONTENTS xxi 2.3. Immune Reconstitution Following PR Inhibitor Therapy in Children Genetic Analysis of Protease in Response to Protease Inhibitors Patients Methods Phylogenetic Trees Genotypic Resistance in Protease Genetic Distance in Protease over Time Models for Evolution of Virus with Inhibitor Virus from Other Perspectives Variability in env Region of the Virus Genome Genetic Analysis and Reservoirs of Viruses References Gene Therapy and HIV-1 Infection: Experimental Approaches, Shortcomings, and Possible Solutions RALPH DORNBURG and ROGER POMERANTZ 1. HlV-1 Infection and Conventional Pharmaceutical Agents Antisense RNAs and Ribozymes RNA Decoys Transdominant Mutant Proteins Toxic Genes CD4 as Decoy Single-Chain Antibodies Gene Delivery of Antiviral Agents Other New Potential Vector Systems Other Potential Problems References Pediatric HIV: Antiretroviral Therapy ROBERT P. NELSON, JR., PATRICIA J. EMMANUEL, and MAITE DE LA MORENA 1. Introduction Antiretroviral Agents Nucleoside Analogue Reverse Transcriptase Inhibitors

20 xxii CONTENTS 2.2. Nonnucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Nucleotide Reverse Transcriptase Inhibitor Pediatric Antiretroviral Treatment Identification of Perinatal HIV Exposure HIV Diagnosis in Infants Immunological Monitoring in Children Monitoring HIV RNA in Children Initiation of Antiretroviral Therapy Choice of Initial Antiretroviral Therapy Changes in Antiretroviral Therapy Duration of Therapy Salvage Antiretroviral Therapy Appendix References Index