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The Herpesviruses

'You damn sadist/said mr cummings 'you try to make people think. ' -Ezra Pound (Canto 89) What makes herpesviruses unique? It is certainly not the size of their genomes or the individual features of their reproductive cycle, although in toto striking features that are exclusive to the herpesviruses abound. Unquestionably, the pre-eminent feature is the relationship of herpes- viruses with their natural hosts. As described in preceding volumes, all herpesviruses seem to be able to colonize and to remain in a latent, nonproductive form for life of their hosts. Once established in the host, the relationship is best described as that of an armed truce. What happens when this truce breaks down or when the host encounters the virus for the first time is the subject of this volume. We have focused primarily on the five human herpesviruses [herpes simplex virus 1 (HSV-l), herpes simplex virus 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV) and Epstein-Barr virus (EBV)] because much more is known about them than about any other herpesviruses, and because it is of interest to compare both the diversity of manifestations of infections with human herpesviruses and the spectrum of human responses to these viruses. This volume summarizes the current knowledge of the pathogenesis and immunobiology of herpesvirus infections in man and describes new and developing approaches to prophylaxis and treatment. It contains con- tributions from distinguished research scientists presently engaged at the forefront of these scientific investigations.
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Table of Contents

1 The Natural History of Genital Herpes Simplex Virus: Perspectives on an Increasing Problem.- I. Introduction.- II. History.- III. Epidemiology of Genital Herpes.- A. Prevalence of Genital HSV Infections.- B. Evidence for an Increasing Prevalence of Infection.- C. Prevalence of HSV Antibody.- D. Incidence of Genital Herpes.- E. Comment.- IV. Clinical Manifestations of Genital Herpes.- A. First Episodes of Genital Herpes.- B. Primary Genital Herpes.- C. Complications of Genital Herpes.- D. Summary of the Clinical Course of First Episodes of Genital Herpes.- E. Future Directions for Research on the Clinical Manifestations of Genital Herpes.- F. Recurrent Genital Herpes.- G. Other Clinical Syndromes Associated with Genital HSV Infection.- V. Chronicity of Genital HSV Infections.- VI. Sexual Transmission of Genital HSV.- VII. Conclusions.- References.- 2 Natural Resistance Mechanisms in Herpes Simplex Virus Infections.- I. Introduction.- II. Genetic Resistance to Lethal HSV-1 in the Mouse.- III. Genetic Resistance to Lethal HSV-2 in the Mouse.- IV. Genetic Resistance to HSV-2-Induced Hepatitis.- V. Macrophages.- A. Role of Macrophages in Resistance to HSV-1 in the Mouse.- B. Role of Macrophages in Resistance to HSV-2 in the Mouse.- C. Role of Macrophages in Resistance to HSV-2-Induced Hepatitis.- D. Role of Macrophages in Resistance to HSV-1 and HSV-2 in Man.- VI. Natural Killer Cells.- A. Heterogeneity of NK Cells.- B. Cell Lineage of NK(HSV-Fs) Effectors.- C. Role of IFN in NK(HSV-Fs) Response.- D. NK Cells Limit HSV-1 Replication in Vitro.- E. Role of NK Cells in Resistance to HSV-1 in the Mouse.- F. Low NK(HSV-Fs) Function Associated with Susceptibility to Herpesvirus Infections in Man.- VII. Interferon.- A. Role of IFN in Genetic Resistance to HSV-1 in the Mouse.- B. IFN-a-Generating Cells in Man.- C. Role of IFN in Resistance to Herpesvirus Infections in Man.- VIII. Concluding Remarks.- References.- 3 Humoral Response to Herpes Simplex Virus Infections.- I. Introduction.- II. HSV-Specific Antibodies in Human Convalescent Sera.- III. Measurement of HSV-Specific Neutralizing Antibodies.- IV. Measurement of HSV Antibodies by Immunofluorescence.- V. Measurement of HSV-Cytolytic Antibodies.- VI. Measurement of HSV-Precipitating Antibodies.- VII. Measurement of HSV Antibodies with ELISA and RIA.- VIII. Measurement of HSV Antibodies by Immunoblotting.- IX. Immunogenicity of the HSV-1 and HSV-2 Proteins.- X. Measurement of HSV-Specific Antibodies Belonging to the IgM and IgA Classes.- XI. Function of HSV-Specific Antibodies in Vivo.- XII. Conclusion.- References.- 4 The T-Cell-Mediated Immune Response of Mice to Herpes Simplex Virus.- I. Introduction.- II. Evidence for Thymus-Dependent Resistance to Herpes Infections.- A. Use of Athymic Mice and Immunosuppression.- B. Use of B-Cell-Suppressed Mice.- III. T-Cell Subsets Induced in Herpes Infections.- A. Cytotoxic T Lymphocytes.- B. T Cells Mediating Delayed Hypersensitivity.- C. T-Helper Lymphocyte Response.- D. T-Suppressor Cells.- IV. T Cells Involved in Antiherpes Responses in Vivo.- V. Regulation of Immune Responses to Herpes-A Role in Prevention of Immunopathology?.- VI. T-Cell Memory.- VII. Conclusions.- VIII. Appendix: Immunological Terms Used.- References.- 5 Immunopathology of Herpesvirus Infections.- I. Introduction.- II. IgE-Mediated Immunopathology.- III. Immune Complex Immunopathology.- IV. Immunopathology Mediated by T Lymphocytes.- V. Management of Immunopathological Reactions.- References.- 6 Cell-Mediated Immunity in Cytomegalovirus Infections.- I. Introduction.- II. Characteristics of Effector Cell Functions Relevant in CMV Infections.- A. NK Cells and Other Large Granular Lymphocytes.- B. Antibody-Dependent Cell-Mediated Cytotoxicity.- C. Cytotoxic T Cells.- III. Virus-Specific Cytotoxic Lymphocyte Responses during CMV Infections.- IV. Evidence That Virus-Specific Cytotoxic Lymphocytes Determine the Outcome of CMV Infections.- V. Evidence That NK Cells and Other Large Granular Lymphocytes Are Important in CMV Infections.- VI. Causes of Depressed Cytotoxic T-Cell Responses and NK Cell Activity in High-Risk Populations.- VII. Delayed-Type Hypersensitivity Responses to CMV.- VIII. CMV-Induced Immune Suppression.- IX. CMV-Induced in Vitro Lymphocyte Blastogenesis.- X. Cellular Immune Responses to CMV Vaccine.- XI. Conclusion.- References.- 7 In Vivo Studies of Epstein-Barr Virus and Other Lymphotropic Herpesviruses of Primates.- I. Introduction.- II. EBV in New World Primates.- A. Host Range for Disease Induction.- B. Clonality of Tumors in Cotton-Topped Marmosets.- C. Potential Use of Cotton-Topped Marmosets in EBV Vaccine Development.- III. Herpesvirus papio and Lymphoproliferative Disease in Baboons.- A. Background.- B. Virus Isolates.- C. Antibody Patterns to H. papio-Associated Antigens.- D. Presence of Viral DNA in Tumor Tissue and Spleen.- E. Experimental Disease in Cotton-Topped Marmosets.- F. Summary of Features of the Disease and Possible Similarity to Other Diseases of Captive Monkeys.- IV. Other Lymphotropic Herpesviruses of Old World Primates and Their Possible Relationship to Disease.- V. T-Cell-Tropic Herpesviruses.- A. Pathogenicity and Host Range.- B. Lymphocyte Tropism and Antigen Modulation.- C. H. saimiri Tumor Cell Lines.- D. In Vitro Transformation.- VI. Tupaia Herpesviruses.- VII. Summary and Conclusions.- References.- 8 Cell-Mediated Immunity to EBV.- I. Introduction.- II. Inhibition of the in Vitro Growth of B Cells.- III. EBV-Induced Cell Surface Antigens Detected by Lymphocyte Cytotoxicity.- IV. Immunological Memory to EBV-Determined Antigens Detected by Lymphokine Production.- V. EBV-Related Immune Parameters in Pathological Conditions.- References.- 9 Immunobiology of EBV-Associated Cancers.- I. Introduction.- II. Diagnostic Value of Antibodies to EBV Antigens.- III. Prognostic Value of EBV Serology.- VI. Identification and Purification of EBV Proteins.- V. Cellular Immunity.- VI. Conclusions.- References.- 10 Cytomegalovirus Infection after Organ Allografting: Prospects for Immunoprophylaxis.- I. Introduction.- II. Pathogenesis of CMV Disease.- III. Epidemiologic Risk Factors.- A. Infection Due to Blood Products in Seronegative Patients.- B. Transmission of Virus in Transplanted Tissue.- C. Reactivation of Latent Virus.- IV. Prevention of Primary Infection.- A. Donor Selection.- B. Control of Blood Products.- C. Passive Immunoprophylaxis with Plasma or Globulin..- D. CMV Vaccine.- V. Prevention of Virus Reactivation.- A. Interferon.- B. Antiviral Agents.- VI. Immunosuppressive Regimen.- VII. Treatment of CMV Infection.- VIII. Conclusions.- References.- 11 Epstein-Barr Virus and the X-Linked Lymphoproliferative Syndrome.- I. Introduction.- II. Immunopathogenesis of EBV Infection in the Normal Host.- III. X-Linked Lymphoproliferative Syndrome.- A. General Characteristics.- B. Immunologic and Virologie Studies in Males before and during Fatal EBV Infection.- C. Immunologic Studies in Surviving Males.- D. Immunological and Virological Studies in Carrier Females.- IV. Pathogenesis of the X-Linked Lymphoproliferative Syndrome.- V. Treatment of Fulminant EBV Infections.- References.- 12 Abnormal Responses to EBV Infection in Patients with Impairment of the Interferon System.- I. Introduction.- II. Immunological Control of EBV Infection.- III. The IFN System and Its Place in Antiviral Immunity.- IV. Evidence for a Role of IFN in the Control of EBV Infection in Vitro.- V. Evidence for a Role of IFN in the Control of EBV Infection in Patients.- A. IFN Administration in Immunosuppressed Patients.- B. Selective Defects of IFN Secretion.- VI. Chronic Neutropenia Triggered by EBV Infection and Associated with Impaired Activation of NK Cells by IFN.- VII. Conclusion.- References.- 13 Vaccination against Herpes Simplex Virus Infections.- I. Introduction.- II. The Use of Wild-Type Virus.- III. The Use of Inactivated (Killed) Virus.- A. The Placebo Effect.- B. Studies without a Placebo Group.- C. Studies Including a Placebo Group.- IV. Subunit Vaccines.- A. Preparation.- B. Experience in Animals.- C. Experience in Man.- D. Future Trends.- V. Live Vaccines.- A. HSV Mutants.- B. Heterologous Herpesviruses.- C. Antigens Expressed by Non-HSV Viral Vectors.- D. Genetically Engineered HSV.- VI. Conclusion.- References.- 14 CMV Vaccines.- I. Introduction.- II. Donor Selection.- III. Passive CMV Antibody.- IV. Vaccination.- V. Subunit Vaccines.- VI. Interferon.- VII. Summary.- References.- 15 Live Attenuated Varicella Vaccine.- I. Historical Perspective.- II. Development of Varicella Vaccine.- A. First Studies in Japan.- B. Subsequent Studies in Japan.- III. Studies in the United States on Varicella Vaccine.- A. Studies in Normal Children.- B. Studies in Children with an Underlying Malignancy.- IV. Problems Requiring Further Resolution.- A. Persistence of Immunity after Vaccination.- B. Dose of Vaccine Virus Necessary to Induce Immunity.- C. Safety.- V. Logistics of Future Vaccine Use.- A. Potential Vaccine Candidates.- B. Future Planning.- References.- 16 A Subunit Vaccine against Epstein-Barr Virus.- I. Introduction.- A. Immunological Control of EBV Infection.- B. EBV and Human Tumors.- C. Comment.- II. Reasons for an Antiviral Vaccine.- III. EBV Membrane Antigen.- A. Quantification of MA gp340.- B. A Preparation Method for MA gp340.- C. Immunization with MA gp340 Using Novel Adjuvants..- D. Structure of MA gp340.- IV. Discussion.- References.- 17 A Perspective on the Therapy of Human Herpesvirus Infections.- I. Introduction.- A. Development of Antivirals for Clinical Evaluation.- B. Antiviral Drugs.- II. The Road to Controlled Trials.- A. Vidarabine.- B. Acyclovir.- III. Clinical Trials.- A. Herpes Simplex Keratoconjunctivitis.- B. Cutaneous HSV Infections.- C. Herpes Simplex Encephalitis.- D. Neonatal HSV Infections.- E. VZV Infections.- IV. Conclusion.- References.- 18 The Role of Interferon in Immunity and Prophylaxis.- I. Introduction.- II. The Interferons.- III. Antiviral Mechanisms of Interferon.- IV. Immunolomodulatory Effects of Interferon.- A. Immunoenhancement.- B. Immunosuppression.- V. Interferon and the Herpesviruses.- A. Cytomegalovirus.- B. Varicella-Zoster Virus.- C. Esptein-Barr Virus.- D. Herpes Simplex Virus.- VI. Prophylaxis and Therapy with Interferon.- A. Animal Studies.- B. Human Studies.- VII. Future Directions.- References.- 19 Effects of Immunopotentiating and Immunomodulating Agents on Experimental and Clinical Herpesvirus Infections.- I. Introduction.- II. Microbial Agents and Substances of Microbial Origin.- III. Transfer Factor.- IV. Thymic Hormones (Factors).- V. Synthetic Interferon Inducers.- VI. Levamisole.- VII. Inosiplex.- VIII. Miscellaneous Immunomodulating Agents.- IX. Conclusion.- References.

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