Herpesviruses and Immunity

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1 Herpesviruses and Immunity

2 INFECTIOUS AGENTS AND PATHOGENESIS Series Editors: Mauro Bendinelli, University of Pisa Herman Friedman, University of South Florida College of Medicine Recent volumes in the series: DNA TUMOR VIRUSES Oncogenic Mechanisms Edited by Giuseppe 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 MICROORGANISMS AND AUTOIMMUNE DISEASES Edited by Herman Friedman, Noel R. Rose, and Mauro Bendinelli NEUROPATHOGENIC VIRUSES AND IMMUNITY Edited by Steven Specter, Mauro Bendinelli, and Herman Friedman 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 INFECTIOUSAGENTS Edited by Steven Specter, Mauro Bendinelli, and Herman Friedman RICKETTSIAL INFECTION AND IMMUNITY Edited by Burt Anderson, Herman Friedman, and Mauro Bendinelli VIRUS-INDUCED IMMUNOSUPPRESSION Edited by Steven Specter, Mauro Bendinelli, and Herman Friedman 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 Herpesviruses and Immunity Edited by Peter G. Medveczky and Herman Friedman University of South Florida College of Medicine Tampa, Florida and Mauro Bendinelli University of Pisa Pisa, Italy Kluwer Academic Publishers. New York / Boston / Dordrecht / London / Moscow

4 ebook ISBN: Print ISBN: X 2002 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow All rights reserved No part of this ebook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's ebookstore at:

5 Contributors JENS-CHRISTIAN ALBRECHT. Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany ANN M. ARVIN. Department of Pediatrics and Microbiology/Immunology, Stanford University School of Medicine, Stanford, California SALLY S. ATHERTON. Department of Cellular and Structural Biology, University of Texas Health Sciences Center at SanAntonio, San Antonio, Texas DAVID C. BLOOM. Department of Microbiology,Arizona State University, Tempe, Arizona BERNADETTE DUTIA. Department of Veterinary Pathology, The University of Edinburgh, Summerhall, Edinburgh EH9 1 QH, Scotland BERNHARD FLECKENSTEIN. Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany PETER GECK Department of Anatomy and Cellular Biology, Tufts University Health Science Schools, Boston, Massachusetts HARTMUT HENGEL Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Lehrstuhl Virologie, Ludwig-Maximilians-Universität München, D München, Germany GEORGE KLEIN Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, S Stockholm, Sweden ULRICH H. KOSZINOWSKI Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Lehrstuhl Virologie, Ludwig-Maximilians- Universität München, D München, Germany V

6 vi CONTRIBUTORS TAKESHI KURATA. Department of Pathology, National Institute of Infectious Diseases, Tokyo 162, Japan PATRICK S. MOORE Division of Epidemiology, Columbia University School of Public Health, New York, New York ANDREW J. MORGAN Department of Pathology and Microbiology, School of Medical Science, University of Bristol, Bristol BS8 ltd, England ANTHONY A. NASH. Department of Veterinary Pathology, The University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Scotland FRANK NEIPEL Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany SONJA J. OLSEN Division of Epidemiology, Columbia University School of Public Health, New York, New York BERNARD ROIZMAN The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois BARRY T. ROUSE Department of Microbiology, University of Tennessee, Knoxville, Tennessee TAKESHI SAIRENJI Department of Biosignaling, School of Life Science, Faculty of Medicine, Tottori University, Yonago 683; and Department of Pathology, National Institute of Infectious Diseases, Tokyo 162, Japan JAMES P. STEWART Department of VeterinaryPathology, The University of Edinburgh, Summerhall, Edinburgh EH9 1 QH, Scotland DAVID A. THORLEY-LAWSON Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts EDWARD J. USHERWOOD Department of Veterinary Pathology, The University of Edinburgh, Summerhall, Edinburgh EH9 1 QH, Scotland; present address: Department of Immunology, St. Jude Children s Research Hospital, Memphis, Tennessee EDWARD K. WAGNER Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California

7 CONTRIBUTORS vii PATRICIA L. WARD The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, Chicago, Illinois HANS J. WOLF. Institut für Mikrobiologie und Hygiene der Medizinischen, Fakultät der Universität Regensberg, D Regensberg, Germany

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 much cooperationbetweenclinicians 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. ix M. Bendinelli H. Friedman

9 Preface Although virology and immunology are now considered separate disciplines, history shows that these areas of investigation always overlapped and one cannot really exist without the other. This trend has become particularly significant and fruitful in the past few years in the area of herpesvirus research. The genomes of the most important herpesviruses have been sequenced, a significant portion of their genes have been identified, and many secrets of regulation of gene expression have been unraveled. Now this progress sets the stage for a true revolution in herpesvirus research: analysis of interactions between the host and the virus. Because herpesviruses can induce, suppress, and fool the immune system, the most productive herpesvirologists are also expert immunologists, and the current results of this interdisciplinary effort are truly remarkable. Because herpesviruses cause many important human diseases, the development of vaccines against these agents is a very significant goal. This effort is also very challenging because of the complexity of herpesviruses and the lack of sufficient information about immune responses. The remarkable ability of herpesviruses to escape immune responses is another feature that brings immunology and virology together. Herpesviruses encode many proteins that interact with and down-regulate some key elements of the immune system. This property of herpesviruses represents a major challenge in developing strategies against these viruses. On the positive side, these viral proteins also provide novel tools for analyzing specific immune reactions and molecular mechanisms. The gamma subgroup of herpesviruses have two additional links to immunology. These viruses undergo latency in immune cells and, in some instances, participate in oncogenic transformation of T or B cells. Moreover, these viruses encode several genes transduced from the host, such as lymphokines, cellular receptors, and complement control genes. Herpesviruses probably use these pirated protein products of the immune system to aid their survival in the infected host. xi

10 xii PREFACE The aim of this book is to present reviews by internationally renowned herpesvirus virologists and immunologists summarizing their work and some of the exciting newer developments in the field of herpes virology. The book is not intended to be a comprehensive work on herpesviruses but is designed to provide an in-depth analysis of cutting-edge areas of herpesvirus research. For example, the first chapter by Drs. Patricia Ward and Bernard Roizman of The University of Chicago describes evasive strategies of human herpesviruses against host defenses. The immunopathology of herpesvirus infection is discussed by Drs. Barry Rouse and Sally Atherton. Then Drs. Edward Wagner and David Bloom discuss gene expression by herpesviruses during latent infections and reactivation. Dr. Peter Geck (Chapter 4) and Drs. Sonja Olsen and Patrick Moore (Chapter 5) describe Kaposi's sarcoma-associated herpesvirus and herpesvirus saimiri effects on T lymphocytes and lymphokines. There is then a review of the immunobiology of murine gamma herpesvirus by Drs. Stewart, Usherwood, Dutia, and Nash. Dr. George Klein (Chapter 7) and Drs. Takeshi Sairenji and Takeshi Karada (Chapter 8) discuss the Epstein Barr virus infection and discuss the role of the immune response and its role in induction of tumors. Dr. David A. Thorley- Lawson discusses EB virus persistence in vivo and to evasion of the immune response. Drs. Wolf and Morgan provide a summary regarding EBV vaccine development. Drs. Hartmut Hengel and Ulrich H. Koszinowski discuss cytomegalovirus effects on MHC class I functions. Dr. Ann Arvin discusses cellular immunity and its role in controlling varicella-zoster virus infection. Drs. Jens- Christian Albrecht, Frank Neipel, and Bernhard Fleckenstein discuss the effects of rhadinoviruses on the complement system of the immune response. It is anticipated by the editors of this volume that the readers of the book will include both immunologists and virologists as well as pre- and postdoctoral students and their mentors. The editors are confident that newer developments in the field of herpesvirus immunology and pathogenesis will continue to stimulate interest in the field of virology and immunology. It is anticipated that the discovery of newer knowledge will occur as rapidly in the future as it has in the past. The editors of the volume are grateful for the time and effort of all contributors. The editors also thank Ms. Ilona M. Friedman for invaluable assistance as editorial coordinator and managing editor for the preparation of this volume. We also thank the editorial staff of Plenum Publishing for their invaluable assistance. Peter G. Medveczky Herman Friedman Mauro Bendinelli

11 Contents 1. Evasion and Obstruction: The Central Strategy of the Interaction of Human Herpesviruses with Host Defenses PATRICIA L.WARD AND BERNARD ROIZMAN 1. Introduction Immune Evasion during Latent Infection Latent HSV-1, HSV-2, and VZV Infections Latent HCMV, HHV-6, and HHV-7 Infections Latent EBV and HHV-8 Infections Immune Evasion during Lytic Infection Interference with Antigenic Presentation Interference with Innate Defense Mechanisms Infection of Cells of the Immune System Role of the Complement Pathway Role of Cytokines Interference with Host Suicide Mechanisms Summary and Conclusions References Immunopathology of Herpesvirus Infections BARRY T. ROUSE AND SALLY S. ATHERTON 1. Introduction Immunopathological Mechanisms against Viruses Immunopathogenesis of HSV Infection of the Cornea xiii

12 xiv CONTENTS 4. Immunopathogenesis of Herpetic Retinal Disease Pathogenesis of Infectious Mononucleosis References HSV Gene Expression during Latent Infection and Reactivation EDWARD K. WAGNER AND DAVID C. BLOOM 1. Introduction The HSV Genome in the Establishment and Maintenance of Latent Infections in Neurons Establishment of Latent Infections in Sensory Neuron Viral Genomes in Latently Infected Neurons Most Latent HSV Genomes in Neurons Are Not Transcriptionally Active HSV Genomes Are Stably Maintained in Latently Infected Neurons HSV Gene Expression during Latent Infection in Neurons The Promoter Controlling HSV Latent-Phase Transcription Analysis of Functional Elements of the HSV-1 Latent-Phase Promoter by Transient Expression Assay Analysis of Latent-Phase Promoter Elements in Vivo Is There a Second Latent-Phase Promoter? The Role of Latent-Phase Transcription in Latency and Reactivation Latent-Phase Transcription Is Required for Efficient Reactivation in in Vivo Models The Region of the Latent-Phase Transcript Important in the Efficient Reactivation Phenotype in Rabbits Is Confined to a Region of 480 bp or Less within Its Extreme 5' End Evidence that Modulation of Expression of LAT during the Latent Phase or at the Initiation of Reactivation Has a Role in Efficient Induction of Virus in the Rabbit Eye Model Latent-Phase Transcription Facilitates but Is Not Required for Efficient Recovery of Infectious Virus from Explanted Latently Infected Murine Ganglia The HSV-1 Latent Phase Transcript May Have a Role in the Efficiency in Establishing Latent Infection in Murine Trigeminal Ganglia... 65

13 CONTENTS xv 5.6. Murine Explant Models Do Not Reveal a Region Critical for Virus Recovery Equivalent to That Characterized for Rabbit Reactivation in Vivo The Mechanism of Action of HSV LAT in Reactivation There Is No Evidence for a Major Antisense-Mediated Repressive Action in Animal Models There Is No Evidence for a Latent-Phase-Expressed Viral Protein Involved in Reactivation Possible cis-acting Mechanisms for the Influence of LAT on Reactivation Does Latent-Phase Transcription Supply an Essential Function to Neurons or Peripheral Cells Initiating Reactivation? References T Cell Activation and Lymphokine Induction in Herpesvirus saimiri Immortalized Cells PETER GECK 1. Introduction The Lymphotropic Gamma Herpesviruses The Biology of H. saimiri The Molecular Environment of H. saimiri Oncogenesis: Signal Transduction in T Cell Activation (Operational Principles, Competence Phase, Progression Phase) Operational Principles of the Cellular Immune Response (Maintenance of Antigenic Integrity, T Cell Activation the Target Pathway for H. saimiri) Competence Phase in T Cell Activation (Antigen Recognition, T Cell Receptor Activation, Signal Transduction, Target Genes) Progression Phase (Cytokine Systems, Cytokine 'Signal Transduction, Target Genes) Characterization of H. saimiri Transformed Lymphocytes Surface Markers Cytokine Profile of H. saimiri Transformed T Cells Functional Analysis of H. saimiritransformed T Lymphocytes The Immunological Profile of H. saimiri Transformed Cells and Implications in Signal Transduction H. saimiri Pathways for T Cell Activation and Cytokine Induction H. saimiri Genes Involved in T Cell Activation Regulation of the stp/tip mrna Expression

14 xvi CONTENTS 4.3. The Function of the tip Protein The Function of the stp Protein (stpa and stpc) Conclusions References Kaposi's Sarcoma-Associated Herpesvirus (KSHV/ HHV8) and the Etiology of KS SONJA J. OLSEN AND PATRICK S. MOORE 1. Introduction Epidemiology Kaposi's Sarcoma Evidence for Causality Transmission Sexual Nonsexual Saliva Vertical Organ Transplantation Conclusion References Immunobiology of Murine Gamma Herpesvirus-68 JAMES P. STEWART, EDWARD J. USHERWOOD, BERNADETTE DUTIA, AND ANTHONY A. NASH 1. Introduction The Virus Aspects of Viral Infection The Viral Genome Drug Sensitivity Infection and Pathogenesis Acute Infection in the Lung Persistent Infection in the Lung Latent Infection in the Spleen Other Consequences of MHV-68 Infection Immunological Events during Infection

15 CONTENTS xvii 4.1. Influence of Adaptive Immune Response Influence of the Innate Immune Response Conclusions References EBV and B Cell Lymphomas GEORGE KLEIN 1. EBV-Associated Proliferative Diseases EBV and Human Malignancy Burkitt s Lymphoma Non-Hodgkin s Lymphoma (NHL) in HIV-Infected Patients Hodgkin s Disease (HD) EBV and T Cell Lymphomas Conclusions References Immune Responses to Epstein Barr Viral Infection TAKESHI SAIRENJI AND TAKESHI KURATA 1. Introduction EBV-Specific Antigens EBNA LMP Induction of Lytic Cycle by Signaling from the Cell Surface EA VCA MA Antibody Response to EBV Infection Immunofluorescence Test Enzyme-Linked Immunosorbent Assay (ELISA) Antibody Responses to EBV-Specific Enzymes Antibody-Mediated Immune Mechanisms Neutralizing Antibodies Modulation of EBV Production with Anti-EBV Antibodies Inhibition of EBV Release by mabs to gp350/ EBV-Induced Autoimmune Responses

16 xviii CONTENTS 6. Conclusion References EBV Persistence in Vivo: Invading and Avoiding the Immune Response DAVID A. THORLEY-LAWSON 1. Introduction Viral Entry and the Establishment of Infection Viral Entry Establishment of the Infection Long-Term Latency The Site of Long-Term Persistence Resting Memory B Cells Maintenance of Long-Term Latency Some Facts and Some Speculation Getting Back out Again: Viral Reactivation More Facts and Speculation Final Remarks Summing Up The Questions that Need to Be Addressed References Epstein-Barr Virus Vaccines HANSJ.WOLFAND ANDREW J. MORGAN 1. Introduction Is an EBV Vaccine Desirable? Rationale for Vaccination of Infants Rationale for Vaccination of Persons Already Infected with EBV Testing an EBV Vaccine Choice of Immunogen Production Systems Choice of Adjuvant Live Recombinant Virus Vector Vaccines Cell-Mediated Immune Responses to gp Human Trials EBV Latent Antigen Vaccines

17 CONTENTS xix 8. Conclusions References Inhibition of MHC Class I Function by Cytomegalovirus HARTMUT HENGEL AND ULRICH H. KOSZINOWSKI 1. Introduction Principles of the Immune Control of CMV Infection The MHC Class I Pathway of Antigen Processing and Presentation CMV Strategies for Immune Escape MCMV Gene Functions Affecting the MHC Class I Pathway of Antigen Presentation The m152 Encoded Glycoprotein Retains MHC Class I Complexes in the ERGIC gp34 of MCMV Binds to MHC Class I Complexes gp48 of MCMV Targets MHC Class I Complexes to the Lysosome for Destruction MCMV Gene Functions Affecting the MHC Class I Pathway of Antigen Presentation The HCMV UL18 Glycoprotein Binds β 2 mandpeptides The HCMV US1 1 Glycoprotein Dislocates MHC Class I Heavy Chains to the Cytosol The HCMV US2 Glycoprotein Transfers MHC Class I Heavy Chains via Sec61 to the Cytosol The HCMV US3-Encoded Glycoprotein Inhibits MHC Class I Transport HCMV US6 Blocks Peptide Translocation by the MHC- Encoded Peptide Transporter TAP1/ HCMV Prevents Antigen Presentation of the72-kda IE Protein Discussion Summary References Cell-Mediated Immunity against Varicella-Zoster Virus ANN M. ARVIN 1. Introduction The Virus

18 xx CONTENTS 3. Methods for Assessing Cellular Immunity to VZV Cell-Mediated Immunity in the Control of Primary VZV Infection Components of the Memory T Cell Response to VZV and Its Protein Specificity Alterations in Memory Cell-Mediated Immunity and Susceptibility to VZV Reactivation Mechanisms for Preserving Memory T Cell Immunity to VZV Cell-Mediated Immunity in the Control of VZV Reactivation Cell-Mediated Immune Responses against VZV Elicited by Primary Immunization with Varicella Vaccine Memory T Cell Immunity to VZV following Immunization and ProtectionagainstVaricella Enhancement of Memory T Cell Immunity by Vaccination of Naturally Immune Individuals Summary References Complement Control Proteins of Rhadinoviruses JENS-CHRISTIAN ALBRECHT, FRANK NEIPEL, AND BERNHARD FLECKENSTEIN 1. Introduction Genomic Organization of Rhadinoviruses The C3 Convertase Inhibitor of H. saimiri The Complement Control Protein of H.ateles The Complement Regulator of Kaposi's Sarcoma-Associated Herpesvirus HHV The Terminal Complement Inhibitor of H. saimiri Concluding Remarks References Index

19 Herpesviruses and Immunity