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This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi’s Sarcoma-associated herpesvirus, cytom-egalovirus, HHV6A, 6B, and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.
Contents
- Contributors
- Preface
- I. Introduction: definition and classification of the human herpesvirusesEditor: Bernard Roizman.
- 1. Overview of classificationAndrew J. Davison.
- 2. Comparative analysis of the genomesAndrew J. Davison.
- 3. Comparative virion structures of human herpesvirusesFenyong Liu and Z. Hong Zhou.
- Introduction
- Different virus-related particles found in infected cells
- Compositions and three-dimensional structural comparisons of alpha, beta and gammaherpesvirus capsids
- Structure and packaging of viral genomic DNA
- Structure and assembly of tegument
- Structure and assembly of viral envelope
- Other constituents in the virions
- Acknowledgments
- References
- 4. Comparative analysis of herpesvirus-common proteinsEdward S. Mocarski Jr.
- 1. Overview of classification
- II.1. Basic virology and viral gene effects on host cell functions: alphaherpesvirusesEditors: Gabriella Campadelli-Fiume and Bernard Roizman.
- 5. Genetic comparison of human alphaherpesvirus genomesJoel D. Baines and Philip E. Pellett.
- 6. Alphaherpes viral genes and their functionsBernard Roizman and Gabriella Campadelli-Fiume.
- 7. Entry of alphaherpesviruses into the cellGabriella Campadelli-Fiume and Laura Menotti.
- 8. Early events pre-initiation of alphaherpes viral gene expressionThomas M. Kristie.
- The HSV IE regulatory domains: multiple sites for differential regulation
- The assembly of the HSV IE enhancer core complex
- Ancillary factors: Sp1 and GABP
- VZV IE gene expression: parallels and divergence
- Regulation of the IE genes: multiple levels and response potentials
- The regulation of the IE genes: reactivation of HSV from the latent state
- Questions and future directions
- Acknowledgments
- References
- 9. Initiation of transcription and RNA synthesis, processing and transport in HSV and VZV infected cellsRozanne M. Sandri-Goldin.
- 10. Alphaherpesvirus DNA replicationJohn Hay and William T. Ruyechan.
- 11. Envelopment of herpes simplex virus nucleocapsids at the inner nuclear membraneJoel D. Baines.
- 12. The egress of alphaherpesviruses from the cellGabriella Campadelli-Fiume.
- 13. The strategy of herpes simplex virus replication and takeover of the host cellBernard Roizman and Brunella Taddeo.
- Introduction
- Gene content, organization, and fundamental design of the viral genome
- Mobilization of cellular proteins for enhanced replication of HSV
- The objectives and general strategy of anti-host functions
- The activation of NF-κB
- Degradation of mRNA in infected cells
- Specific degradation of cellular proteins in wild-type virus-infected cells
- Shut down of the interferon pathways to host resistance to infection
- HSV blocks pro-apoptotic cellular functions
- Conclusions
- Acknowledgments
- References
- 5. Genetic comparison of human alphaherpesvirus genomes
- II.2. Basic virology and viral gene effects on host cell functions: betaherpesvirusesEditor: Edward Mocarski.
- 14. Comparative genome and virion structureAndrew J. Davison and David Bhella.
- 15. Betaherpes viral genes and their functionsE. S. Mocarski Jr.
- 16. Early events in human cytomegalovirus infectionTeresa Compton and Adam Feire.
- 17. Immediate–early viral gene regulation and functionMark F. Stinski and Jeffery L. Meier.
- Introduction
- Betaherpesvirus immediate early genes
- Betaherpesvirus transcriptional enhancers upstream of the MIE genes
- Function of the betaherpesvirus major immediate–early enhancers
- Silencing of the immediate-early genes
- Reactivation of the immediate–early genes
- Betaherpesvirus major immediate–early genes
- Functions of the major immediate–early viral proteins
- Factors that stimulate betaherpesvirus immediate–early gene expression
- Infection and dysregulation of the cell cycle by betaherpesviruses
- Summary
- Acknowledgments
- References
- 18. Early viral gene expression and functionElizabeth A. White and Deborah H. Spector.
- Introduction
- Identification of HCMV early genes
- HCMV-mediated changes in the cellular environment prior to early gene expression
- Functions of viral early genes
- Transactivating functions of the major IE proteins
- Additional immediate early proteins have regulatory roles
- UL112–113 transcription is differentially controlled at early and late times
- Multiple cis-acting sequences regulate UL54 expression
- UL4 expression is controlled at the transcriptional and translational levels
- Human herpesviruses 6 and 7
- Conclusions
- References
- 19. DNA synthesis and late viral gene expressionDavid G. Anders, Julie A. Kerry, and Gregory S. Pari.
- 20. Maturation and egressBill Britt.
- 21. Viral modulation of the host response to infectionA. Louise McCormick and Edward S. Mocarski Jr.
- 14. Comparative genome and virion structure
- II.3. Basic virology and viral gene effects on host cell functions: gammaherpesvirusesEditor: Patrick S. Moore.
- 22. Introduction to the human γ-herpesvirusesRichard Longnecker and Frank Neipel.
- Introduction
- The γ-herpesvirus family
- The discovery of Epstein–Barr virus (EBV)
- Human disease associated with EBV infection
- EBV life cycle
- The discovery of Kaposi’s sarcoma-associated herpesvirus (KSHV)
- KSHV life cycle
- Human disease associated with KSHV infection
- Phylogenetic relationship between EBV, KSHV, and non-human γ-herpesvirus genomes
- Human γ-herpesviruses genomes
- Characteristics of the γ-herpesvirus virion
- Conclusions
- Acknowledgments
- General historical reading
- References
- 23. Gammaherpesviruses entry and early events during infectionBala Chandran and Lindsey Hutt-Fletcher.
- 24. Maintenance and replication during latencyPaul M. Lieberman, Jianhong Hu, and Rolf Renne.
- Introduction
- EBV (lymphocryptovirus)
- Properties of the episomal latent viral genome
- Chromatin organization of the latent episome
- DNA methylation of latent EBV
- Molecular biology of OriP
- Properties of EBNA 1
- Cellular proteins that interact with EBNA 1
- Cellular proteins that interact with OriP
- Mechanism of OriP- DNA replication
- Mechanism of viral chromosome replication
- Mechanisms of plasmid segregation
- KSHV (Rhadinovirus)
- The KSHV episome in latently infected cells
- Properties of the latency-associated nuclear antigen (LANA)
- Latent DNA replication and segregation
- Summary
- References
- 25. Reactivation and lytic replication of EBVShannon C. Kenney.
- Viral pathogenesis
- Activation of lytic EBV infection
- EBV immediate-early proteins
- Early lytic EBV gene regulation
- Early lytic EBV gene products
- Viral replication
- Late viral gene regulation
- Late viral proteins
- Viral assembly and egress
- Treatment of lytic EBV infection
- Lytic induction as a strategy for treating EBV -positive tumors
- Unresolved issues for the future
- Acknowledgment
- References
- 26. Reactivation and lytic replication of KSHVDavid M. Lukac and Yan Yuan.
- Overview: goals of lytic replication
- Lytic reactivation of KSHV is a critical pathogenic step in development of KS and other human diseases
- The immune system tempers lytic reactivation of KSHV and KS development
- MHV-68 is a model for immune control of gamma-herpesvirus reactivation from latency
- Sites of latency and reservoirs for viral amplification in vivo
- Primary effusion lymphoma (PEL) cells: a tissue culture model for KSHV latency and reactivation
- Kinetic classification of KHSV lytic gene expression
- ORF50/Rta is the viral lytic switch protein
- Signals that control lytic reactivation of KSHV
- Lytic replication and interactions with the host cell
- Regulation of lytic DNA replication
- Late genes and KSHV virion structure
- Perspectives
- References
- 27. EBV gene expression and regulationLawrence S. Young, John R. Arrand, and Paul G. Murray.
- Introduction
- Virus and genome structure
- EBV latency in vitro and in vivo
- Other forms of EBV latency
- EBV replication/the lytic cascade
- Functions and associated properties of lytic cycle gene products
- EBV persistence in vivo
- EBV strain variation
- Function of the EBV latent genes: from persistence to pathology
- EBNA1
- EBNA2
- EBNA3 family
- EBNA-LP
- LMP1
- LMP2
- EBERs
- BARTs
- MicroRNAs
- Conclusions
- References
- 28. KSHV gene expression and regulationThomas F. Schulz and Yuan Chang.
- 29. Effects on apoptosis, cell cycle and transformation, and comparative aspects of EBV with other known DNA tumor virusesGeorge Klein and Ingemar Ernberg.
- Viral strategy at the molecular level as a tumor risk factor
- Three types of virus–host cell interactions may carry a risk
- Early history: up and down
- Up again, and how!
- Classes of experimental tumor viruses
- What does the type of virus-cell interaction tell us about tumorigenic risk?
- EBV exploits B-cell specific regulatory mechanisms and signals
- Growth transformation associated EBV encoded proteins
- The latent membrane proteins (LMP) of EBV
- EBV and Burkitt lymphoma (BL)
- Hodgkin’s lymphoma (HL)
- EBV and nasopharyngeal carcinoma
- Viral expression in carcinoma cells, cell behavior and host relationships in NPC
- Immune surveillance and the oncogenic herpesviruses – the role of immunological “anticipation”
- Double HHV8/EBV carrying PEL cells
- References
- 30. KSHV manipulation of the cell cycle and apoptosisPatrick S. Moore.
- 31. Human gammaherpesvirus immune evasion strategiesRobert E. Means, Sabine M. Lang, and Jae U. Jung.
- 22. Introduction to the human γ-herpesviruses
- III.1. Pathogenesis, clinical disease, host response, and epidemiology: alphaherpes virusesEditors: Ann Arvin and Richard Whitley.
- 32. Pathogenesis and diseaseRichard Whitley, David W. Kimberlin, and Charles G. Prober.
- Pathogenesis
- Unique biologic properties of HSV that influence pathogenesis
- Pathology
- Pathology of central nervous system disease
- Impact of host response to infection on disease
- Orolabial infection
- Genital infection
- Keratoconjunctivitis
- Cutaneous infections
- Central nervous system infections
- Neonatal infection
- Infection in compromised hosts
- Acknowledgment
- References
- 33. Molecular basis of HSV latency and reactivationChris M. Preston and Stacey Efstathiou.
- 34. Immunobiology and host responseDavid M. Koelle.
- Introduction
- HSV interactions with dendritic cells
- CD8 T-cell responses to HSV
- CD4 T-cell responses to HSV
- T-cell costimulation and HSV
- Antibody responses to HSV
- Innate immunity
- Immunomodulators and HSV
- Chemokines
- NK cells
- NKT cells
- TCRγδ cells
- Additional interactions between HSV and the immune system
- Summary
- References
- 35. Immunopathological aspects of HSV infectionKaustuv Banerjee and Barry T. Rouse.
- 36. Persistence in the population: epidemiology, transmissionAnna Wald and Lawrence Corey.
- 32. Pathogenesis and disease
- III.2. Pathogenesis, clinical disease, host response, and epidemiology: alphaherpes viruses VZVEditors: Ann Arvin and Richard Whitley.
- 37. VZV: pathogenesis and the disease consequences of primary infectionJennifer Moffat, Chia-Chi Ku, Leigh Zerboni, Marvin Sommer, and Ann Arvin.
- Introduction
- Systems for evaluating determinants of VZV pathogenesis in human skin and T-cells
- Effects of VZV replication on cellular cyclin-dependent kinases and cyclins
- Investigation of events in the pathogenesis of primary VZV infection in the SCIDhu model
- The role of VZV glycoproteins in T-cell and skin tropism
- Glycoprotein C
- Glycoprotein E
- Glycoprotein I
- The role of regulatory proteins and viral kinases in T-cell and skin tropism
- IE62 protein
- IE63 protein
- ORF64 protein
- ORF10 protein
- ORF47 protein
- ORF66 protein
- Disease consequences of primary VZV infection in healthy and immunocompromised hosts
- Varicella in the immunocompromised host
- Varicella in pregnancy and the newborn
- Summary
- References
- 38. VZV: molecular basis of persistence (latency and reactivation)Jeffrey I. Cohen.
- Site of VZV latency
- Quantification of VZV DNA load during latency
- Animal models for VZV latency
- VZV transcripts expressed during latency
- VZV proteins expressed during latency
- Function of VZV latency-associated proteins
- VZV genes required for establishment of latent infection
- In vitro models for VZV latency
- Reactivation of VZV
- Comparison of VZV latency with that of other alphaherpesviruses
- Is the large number of transcripts in VZV latency due to reactivation?
- Models for VZV latency
- VZV proteins localize to the cytoplasm, instead of the nucleus of neurons and thus are unable to carry out their activities
- VZV proteins have different activities in neurons than in permissive cells due to differences in cellular proteins
- Future directions
- References
- 39. VZV: immunobiology and host responseAnn Arvin and Allison Abendroth.
- 40. VSV: persistence in the populationJane Seward and Aisha Jumaan.
- 37. VZV: pathogenesis and the disease consequences of primary infection
- III.3. Pathogenesis, clinical disease, host response, and epidemiology: betaherpesvirusesEditors: Ann Arvin and Richard Whitley.
- 41. Virus entry into host, establishment of infection, spread in host, mechanisms of tissue damageWilliam Britt.
- 42. Molecular basis of persistence and latencyMichael A. Jarvis and Jay A. Nelson.
- 43. Immunobiology and host responseMark R. Wills, Andrew J. Carmichael, J. H. Sinclair, and J. G. Patrick Sissons.
- 44. Persistence in the population: epidemiology and transmissonSuresh B. Boppana and Karen B. Fowler.
- Introduction
- Epidemiology of HCMV infection
- Transmission of HCMV by mothers to infants: perinatal infections
- Children-to-children transmission of HCMV
- Transmission of HCMV by children to parents
- HCMV transmission through sexual activity
- Transmission of HCMV to child-care providers
- Transmission of CMV in health-care settings
- Transfusion acquired HCMV infection
- Transplantation and HCMV infection
- HCMV transmission from artificial insemination by donor semen
- Summary
- References
- 45. HCMV persistence in the population: potential transplacental transmissionLenore Pereira, Ekaterina Maidji, Susan J. Fisher, Susan McDonagh, and Takako Tabata.
- 41. Virus entry into host, establishment of infection, spread in host, mechanisms of tissue damage
- III.4. HHV-6A, 6B, and 7Editors: Ann Arvin and Richard Whitley.
- 46. HHV-6A, 6B, and 7: pathogenesis, host response, and clinical diseaseYasuko Mori and Koichi Yamanishi.
- 47. HHV-6A, 6B, and 7: molecular basis of latency and reactivationKazuhiro Kondo and Koichi Yamanishi.
- 48. HHV-6A, 6B, and 7: immunobiology and host responseFu-Zhang Wang and Philip E. Pellett.
- 49. HHV-6A, 6B, and 7: persistence in the population, epidemiology and transmissionVincent C Emery and Duncan A. Clark.
- 46. HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease
- III.5. Pathogenesis, clinical disease, host response, and epidemiology: gammaherpesvirusesEditor: Patrick S. Moore.
- 50. Clinical and pathological aspects of EBV and KSHV infectionRichard F. Ambinder and Ethel Cesarman.
- 51. EBV: immunobiology and host responseDenis J. Moss, Scott R. Burrows, and Rajiv Khanna.
- Introduction
- Response during acute infection
- Response in healthy virus carriers
- Role of CD4+ and CD8+ CTL in control of EBV infection
- Role of CTL effector cells in resolution of acute IM
- T-cell receptor usage
- Virus-driven immune modulation
- T-cell control of EBV-associated malignancies
- Future prospects for an EBV vaccine
- References
- 52. Immunobiology and host response to KSHV infectionDimitrios Lagos and Chris Boshoff.
- 53. The epidemiology of EBV and its association with malignant diseaseHenrik Hjalgrim, Jeppe Friborg, and Mads Melbye.
- 54. The epidemiology of KSHV and its association with malignant diseaseJeffrey N. Martin.
- 55. EBV-induced oncogenesisNancy Raab-Traub.
- 56. KSHV-induced oncogenesisDon Ganem.
- 50. Clinical and pathological aspects of EBV and KSHV infection
- IV. Non-human primate herpesvirusesEditors: Ann Arvin, Patrick S. Moore, and Richard Whitley.
- 57. Monkey B virusJulia Hilliard.
- 58. Simian varicella virusRavi Mahalingam and Donald H. Gilden.
- 59. Primate betaherpesvirusesPeter A. Barry and W. L. William Chang.
- 60. Gammaherpesviruses of New World primatesBernhard Fleckenstein and Armin Ensser.
- 61. EBV and KSHV – related herpesviruses in non-human primatesDamania Blossom.
- Introduction
- Nomenclature
- Evolution of New and Old World lymphocryptoviruses
- Lymphocryptoviruses of Old World monkeys
- The rhesus LCV genome
- Latency, immune-modulatory and transforming genes of rhesus LCV
- Rhesus LCV as an animal model system for EBV
- Other lymphocryptoviruses in Old World primates
- Lymphocryptoviruses of New World monkeys
- New World primates as an animal model system for EBV
- Evolution of New and Old World rhadinoviruses
- Rhadinoviruses of Old World primates
- Retroperitoneal fibromatosis herpesviruses: RFHVMm and RFHVMn
- Rhesus monkey rhadinovirus (RRV)
- RRV as an animal model system for KSHV
- Conclusions
- Acknowledgments
- References
- 57. Monkey B virus
- V. Subversion of adaptive immunityEditors: Richard Whitley and Ann Arvin.
- 62. Herpesvirus evasion of T-cell immunityBenjamin E. Gewurz, Jatin M. Vyas, and Hidde L. Ploegh.
- 63. Subversion of innate and adaptive immunity: immune evasion from antibody and complementLauren M. Hook and Harvey M. Friedman.
- Role of the herpesvirus IgG Fc receptor in immune evasion
- Herpes simplex virus FcγR
- Human CMV FcγR
- Varicella zoster FcγR
- vFcγRs on non-human mammalian herpesviruses
- Summary of vFcγR studies
- Role of the herpesvirus complement receptors in immune evasion
- Strategies employed by human herpesviruses to evade complement immunity
- Strategies employed by non-human mammalian herpesviruses to evade complement immunity
- Summary of viral complement regulatory proteins
- References
- 62. Herpesvirus evasion of T-cell immunity
- VI. Antiviral therapyEditors: Ann Arvin and Richard Whitley.
- 64. Antiviral therapy of HSV-1 and -2David W. Kimberlin and Richard J. Whitley.
- 65. Antiviral therapy of varicella-zoster virus infectionsJohn W. Gnann Jr.
- 66. Antiviral therapy for human cytomegalovirusPaul D. Griffiths and Michael Boeckh.
- 67. New approaches to antiviral drug discovery (genomics/proteomics)Mark N. Prichard.
- Introduction
- Development of bioinformatics and computational tools
- Impact of genomics and related fields on herpesvirus research
- New resources for use in drug discovery
- Application of new technologies to cell-based antiviral assays
- Application of new technologies to biochemical assays
- Application of new technologies to functional assays
- Application of new technologies to characterize mechanism of action and spectrum of activity
- Conclusions
- Acknowledgment
- References
- 68. Candidate anti-herpesviral drugs; mechanisms of action and resistanceKaren K. Biron.
- The drug development process: an overview
- Host cell targets as an approach to virus inhibition
- Antiviral targets in early replication events
- Antiviral targets in the herpesvirus DNA replication complex
- Inhibitors of DNA processing and packaging
- Antivirals with activity against EBV, HHV-6, HHV-7, and HHV-8
- Conclusions
- References
- 64. Antiviral therapy of HSV-1 and -2
- VII. Vaccines and immunotherapyEditors: Ann Arvin and Koichi Yamanishi.
- 69. Herpes simplex vaccinesGeorge Kemble and Richard Spaete.
- 70. Varicella-zoster vaccineAnne A. Gershon.
- Varicella vaccines: background
- History of development of the live attenuated vaccine
- Virology of the attenuated Oka strain of VZV
- Safety of the varicella vaccine for healthy individuals
- Immunogenicity of varicella vaccine in healthy children and adolescents
- Efficacy and post-licensure effectiveness of varicella vaccine
- Considerations of vaccine use
- Persistent questions regarding varicella vaccine
- Does immunity to varicella wane with time after immunization?
- Zoster: effects and potential effects on its incidence in the vaccine era
- Vaccination to prevent zoster in the elderly
- Use of inactivated varicella vaccine in patients at high risk to develop zoster
- Recent developments
- Conclusions
- References
- 71. Human cytomegalovirus vaccinesThomas C. Heineman.
- 72. Epstein–barr virus vaccinesAndrew J. Morgan and Rajiv Khanna.
- 73. DNA vaccines for human herpesvirusesThomas G. Evans and Mary Wloch.
- 74. Adoptive immunotherapy for herpesvirusesAnn M. Leen, Uluhan Sili, Catherine M. Bollard, and Cliona M. Rooney.
- Introduction
- Therapy for herpesvirus-related infections and diseases
- Cytomegalovirus
- Epstein–Barr virus
- T-cell activation
- Strategies for producing T-cells for adoptive immunotherapy
- Adoptive immunotherapy for cytomegalovirus
- Adoptive immunotherapy for EBV post-transplant lymphoproliferation disease
- Adoptive immunotherapy for EBV post-solid organ transplant
- Adoptive transfer of EBV-specific CTL for Hodgkin’s lymphoma
- Adoptive transfer of EBV-specific CTL for nasopharyngeal carcinoma
- Multivirus-specific CTL lines
- CMV and EBV immunotherapy in HIV positive individuals
- Alternative approaches for activating virus-specific CTLs
- Conclusions and future considerations
- References
- 75. Immunotherapy of HSV infections – antibody deliveryDavid M. Kimberlin.
- 69. Herpes simplex vaccines
- VIII. Herpesviruses as therapeutic agentsEditors: Richard Whitley and Bernard Roizman.
- 76. Herpesviruses as therapeutic agentsFrank Tufaro and James M. Markert.
- Introduction
- Properties of therapeutic HSV vectors
- Properties of non-replicating HSV vectors for therapeutic use
- Use of HSV vectors to modify the nervous system
- Towards optimizing HSV vectors for therapeutic use
- Non-replicating vectors: current trends
- Oncolytic HSV
- Oncolytic HSV: current directions
- References
- 76. Herpesviruses as therapeutic agents
- Plates
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