Human Herpesviruses Biology Therapy and Immunoprophylaxis 1st Edition by Ann Arvin ,Gabriella Campadelli Fiume ,Edward Mocarski ,Patrick S Moore ,Bernard Roizman ,Richard Whitley ,Koichi Yamanishi ISBN 0397516932 978-0397516933

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ISBN 10:0397516932 

ISBN 13:978-0397516933

Author: Ann Arvin,Gabriella Campadelli-Fiume,Edward Mocarski,Patrick S.Moore,Bernard Roizman,Richard Whitley,Koichi Yamanishi

This definitive and comprehensive account of the human herpes viruses 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, cytomegalovirus and varicella-zoster virus. The diseases 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 if 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 and the volume is fully up to date both scientifically and in terms of clinical guidelines for patient care. The text is generously illustrated throughout and fully referenced to the latest research and developments.

Table of contents: 

Part I Introduction: definition and classification of the human herpesviruses

1 Overview of classification

Introduction

Morphological criteria

Serological criteria

Biological criteria

Genomic criteria

Species definition

Acknowledgment

REFERENCES

2 Comparative analysis of the genomes

Introduction

Genome structures

Genome sequences

Gene content

Genome comparisons and evolution

Three major groups

The mammalian herpesvirus group

The Alphaherpesvirinae subfamily

Outlook

Acknowledgment

REFERENCES

3 Comparative virion structures of human herpesviruses

Introduction

Different virus-related particles found in infected cells

Summary of virion assembly pathway

Different virus-like particles secreted from infected cells

Different capsid-like structures inside the infected cells

Assembly of viral capsid

Compositions and three-dimensional structural comparisons of alpha, beta and gammaherpesvirus capsid

Structure and packaging of viral genomic DNA

Structure and assembly of tegument

Composition of viral tegument

Comparative structure of viral tegument

Overview of tegument structure

Tegument structure of HSV-1

Tegument structure of CMV

Structure and assembly of viral envelope

Other constituents in the virions

Acknowledgments

REFERENCES

4 Comparative analysis of herpesvirus-common proteins

Introduction

Virion structural proteins

Entry into host cells

Regulation of gene expression and replication

Viral DNA synthesis and nucleotide metabolism

Capsid assembly and DNA encapsidation

Maturation

REFERENCES

Part II Basic virology and viral gene effects on host cell functions: alphaherpesviruses

5 Genetic comparison of human alphaherpesvirus genomes

VZV genes that are absent from HSV genomes

L component genes unique to the simplexviruses

S component genes unique to the human simplexviruses

REFERENCES

6 Alphaherpes viral genes and their functions

Introduction

Acknowledgments

REFERENCES

7 Entry of alphaherpesviruses into the cell

Introduction

The membrane proteins

HSV

Attachment to cells

Interaction of gD with its receptors

gD

Receptors

Execution of membrane fusion and its control

The glycoproteins that execute fusion

gH –gL

gB

The quartet of gD, gB, gH and gL assemble into a complex at virus entry

The proteins that negatively control fusion

gB

gK

UL20

Nucleocapsid transport to the nuclear pore

VZV

Is VZV gE a substitute for functions of HSV gD?

Endocytosis of the VZV glycoproteins gE, gB, gH, and the negative regulation of fusion

Acknowledgments

REFERENCES

8 Early events pre-initiation of alphaherpes viral gene expression

The HSV IE regulatory domains: multiple sites for differential regulation

The assembly of the HSV IE enhancer core complex

Oct-1

VP16

HCF-1

Ancillary factors: Sp1 and GABP

Sp1

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 ce

Initiation of transcription and RNA synthesis

The alphaherpesviruses, HSV-1 and VZV encode TATA-box containing promoters that are transcribed by t

Viral factors required for the initiation of transcription on HSV-1 and VZV promoters

Viral IE proteins that contribute to the induced expression of viral genes

RNA processing and transport

Concluding remarks

REFERENCES

10 Alphaherpesvirus DNA replication

Structure of the genome

The origins of DNA replication

Location of DNA synthesis

Proteins involved in DNA synthesis

DNA replication and the cell cycle

Maturation and packaging of viral DNA

Recombination

Latency

Future directions

REFERENCES

11 Envelopment of herpes simplex virus nucleocapsids at the inner nuclear membrane

Introduction

Anatomy of the nuclear membrane: it’s all connected

Envelopment at the nuclear membrane

The UL31/UL34 protein complex and the nuclear lamina

Budding from the nuclear membrane

US3: a kinase that phosphorylates UL34 and UL31 proteins

gK

UL11

UL37

Model of nucleocapsid envelopment at the INM

REFERENCES

12 The egress of alphaherpesviruses from the cell

HSV

Single envelopment pathway

Evidence and arguments in favor

Evidence and arguments against

De-envelopment–re-envelopment pathway

Evidence and arguments in favor

Evidence and arguments against

Cell-to-cell spread

gE–gI

US9

VZV

Concluding remarks

Acknowledgments

REFERENCES

13 The strategy of herpes simplex virus replication and takeover of the host cell

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

Part II Basic virology and viral gene effects on host cell functions: betaherpesviruses

14 Comparative genome and virion structure

Introduction

Genome structures

Genes

Genome sequences

Genetic content

Gene duplication

Gene capture

Variation

Gene function

Virion structure

The genome

The capsid

The tegument

Envelope glycoproteins

Additional virion components

REFERENCES

15 Betaherpes viral genes and their functions

Introduction

Virion structural proteins

Entry into host cells

Regulation of gene expression and replication

Viral DNA synthesis and nucleotide metabolism

Capsid assembly and DNA encapsidation

Maturation

Latency

REFERENCES

16 Early events in human cytomegalovirus infection

Introduction

Cellular receptors for HCMV

Entry activated cell signaling

Cellular integrins may serve as coreceptors for betaherpesviruses

Activation of innate immunity during entry

Roles of betaherpesvirus envelope glycoproteins in virus entry

Coordination of entry and innate immune activation

REFERENCES

17 Immediate–early viral gene regulation and function

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

The IE1 proteins

The IE2 proteins

Factors that stimulate betaherpesvirus immediate–early gene expression

Cellular signal transduction events

Virion components

Infection and dysregulation of the cell cycle by betaherpesviruses

Summary

Acknowledgments

REFERENCES

18 Early viral gene expression and function

Introduction

Identification of HCMV early genes

HCMV-mediated changes in the cellular environment prior to early gene expression

Events triggered by the binding of the virus to the host cell

ND10 are sites of genome deposition and IE transcription

Inhibition of apoptosis

Functions of viral early genes

Genes involved directly in viral replication

Preparing the cell for viral DNA replication

Modulation of host immune responses

Transactivating functions of the major IE proteins

Structure and function of the IE1 72 and IE2 86 kDa proteins

In vitro and transient expression assays demonstrating the transactivating functions of the major IE

Mutational analysis of the major IE products in the viral genome

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

HHV-6 IE gene products with regulatory activities

IE-A

IE-B

U94

cis-acting sequences within HHV-6 early promoters

DNA polymerase (U38)

DNA polymerase processivity factor (U27)

Conclusions

REFERENCES

19 DNA synthesis and late viral gene expression

Overview

Betaherpesvirus replication proteins

Helicase–primase complex (UL105, UL70 and UL102)

DNA polymerase (UL54) and polymerase accessory protein (UL44)

Single-stranded DNA binding protein (UL57)

UL84

Origin binding proteins in roseoloviruses

Immediate–early protein IE2–580aa

UL36–38

Betaherpesvirus replication origins

Cytomegalovirus oriLyt

Cytomegalovirus oriLyt structure

oriLyt open reading frames and transcripts

The mechanism of initiation

Roseolovirus replication origins

Latent phase replication

Late gene expression

REFERENCES

20 Maturation and egress

Introduction

Assembly of the capsid

Protein interactions and capsid assembly

Capsid maturation and DNA packaging

Nuclear tegumentation and nuclear egress

Cytoplasmic tegumentation and envelopment

Tegument protein trafficking and incorporation into the particle

Envelope glycoprotein trafficking and envelopment of the particle

REFERENCES

21 Viral modulation of the host response to infection

Modulation of histone deacetylase activity

Modulation of IRF–3

Activation of NK-kB and interferon response genes

Impact on the host cell cycle

Suppression of apoptosis

vMIA (pUL37x1)

vICA (pUL36)

Other cell death suppressors

Alteration of extrinsic cell death pathways during infection

Summary

REFERENCES

Part II Basic virology and viral gene effects on host cell functions: gammaherpesviruses

22 Introduction to the human Gamma-herpesviruses

Introduction

The gamma-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 gamma-herpesvirus genomes

Human gamma-herpesviruses genomes

Characteristics of the gamma-herpesvirus virion

Conclusions

Acknowledgments

GENERAL HISTORICAL READING

REFERENCES

23 Gammaherpesviruses entry and early events during infection

Target cells for EBV

Target cells for KSHV

Virion structure

Virus structural proteins involved in entry

Virus attachment

Attachment of EBV

Attachment of KSHV

Penetration

Penetration by EBV

Penetration by KSHV

Cell surface signaling during entry

Signaling by EBV during the early stages of infection

Signaling by KSHV during the early stages of infection

Cytoplasmic trafficking, delivery of viral genome into the nucleus

Summary

REFERENCES

24 Maintenance and replication during latency

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 EBNA1

C-terminal DNA binding domain

N- terminal domain linking activity

Metaphase chromosome attachment

Transcription regulation

Proteosome inhibition by GA repeats

Cellular proteins that interact with EBNA1

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)

Modular domain structure of LANA

Transcriptional regulation and signaling properties of LANA

Latent DNA replication and segregation

Mechanism of episomal segregation and chromosome tethering

Mapping LANA’s DNA binding motif and DNA binding domain

Identification of a DS-like element within TR

The TR functions as LANA-dependent plasmid origin

Trans-requirements for LANA and interaction with cellular ORC proteins

Summary

EBV and KSHV origins and origin binding proteins: conserved and diverged?

REFERENCES

25 Reactivation and lytic replication of EBV

Viral pathogenesis

Activation of lytic EBV infection

Lytic viral gene cascade

Stimuli that induce lytic EBV infection

Organization of the IE gene region of EBV

Initial steps in viral reactivation

Cellular factors which activate Zp

BZLF1 autoregulation

Negative regulatory elements in Zp

Regulation of Rp

Mechanisms by which TPA and Butyrate activate IE gene transcription

Host cell and viral factors which influence stringency of viral latency

EBV immediate-early proteins

Introduction

BZLF1 transcriptional effects

BZLF1 activation of methylated ZRE motifs

BZLF1 activation of cellular genes

BZLF1 replication function

The BZLF1-knockout virus is less efficient in promoting lymphoproliferative disease in SCID mice

BZLF1 effects on the host cell environment

BZLF1 cell cycle effects

BZLF1 effects on p53

BZLF1 dispersion of PML bodies

BZLF1 effects on the host immune response

The role of BRLF1 in lytic induction

BRLF1-knockout virus phenotype

BRLF1 activation of the cellular fatty acid synthase gene

BRLF1 cell cycle effects

Early lytic EBV gene regulation

Early lytic EBV gene products

Replication proteins

Transcription factors

SM: a protein that regulates RNA transport and stability

Proteins that inhibit cellular apoptosis and immune evasion

A viral kinase

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 KSHV

Overview: goals of lytic replication

Lytic reactivation of KSHV is a critical pathogenic step in development of KS and other human diseas

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

G1 arrest

Apoptosis

Shut-off of host gene expression

Regulation of lytic DNA replication

Origins of lytic DNA replication

K8/KbZIP and ORF50/Rta are origin-binding proteins that are responsible for recruiting pre-replicati

Viral enzymes and accessory factors essential for KSHV ori-Lyt-specific DNA replication and DNA repl

Single-stranded DNA binding protein (SSB)

DNA helicase–primase complex

DNA polymerase and processivity factor

Late genes and KSHV virion structure

Perspectives

REFERENCES

27 EBV gene expression and regulation

Introduction

Virus and genome structure

EBV latency in vitro and in vivo

The lymphoblastoid cell line LCL

Other forms of EBV latency

EBV replication/the lytic cascade

Functions and associated properties of lytic cycle gene products

Early gene products, early antigens, and diagnostic tests

DNA replicative enzymes

The mRNA export factor, BMLF1

Bcl-2-related proteins

BNLF2a

BARF1

Late gene products

Glycoproteins

Structural proteins

Viral interleukin-10

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 regulation

Introduction

Viral gene expression patterns in culture

PEL derived cell lines

Viral gene expression in newly infected cultured endothelial, epithelial or fibroblast cultures

Viral gene expression in vivo

KS lesions

Primary effusion lymphomas

Multicentric Castleman’s disease

Regulation of gene expression

Splicing

Genomic region containing KSHV latent genes and the viral chemokine receptor homologue

Genomic region containing immediate-early genes

vIRF Locus

Terminalmembrane proteins

“Kaposin” locus

Viral microRNAs

Other spliced genes in the KSHV genome

Events leading to the activation of immediate–early and early KSHV genes

Regulation of the lytic cycle by other viral proteins

Other factors that increase lytic viral replication

REFERENCES

29 Effects on apoptosis, cell cycle and transformation, and comparative aspects of EBV with other kn

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?

Human tumor viruses

Epstein-barr virus (EBV)

EBV exploits B-cell specific regulatory mechanisms and signals

Growth transformation associated EBV encoded proteins

EBNA2

EBNA3 family

EBNA 3 (alt: EBNA 3a)

The latent membrane proteins (LMP) of EBV

Latent membrane proteins 1 (LMP1)

LMP2 modulation of signaling in B-cells and epithelial cells

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”

HHV-8 (KSHV)

Double HHV8/EBV carrying PEL cells

Conclusions

REFERENCES

30 KSHV manipulation of the cell cycle and apoptosis

Cell cycle and programmed cell death regulation

Cell cycle dysregulation during viral latency

LANA-1

LANA

Viral Cyclin (vCYC)

Other KSHV mitogenic signaling proteins

Viral G-protein coupled receptor (vGPCR)

K1 Protein

Virus-encoded chemokines and cytokines

KSHV inhibition of apoptosis

Disarming the guardian: p53 inhibition

LANA-1

LANA2/vIRF3

RTA, K-bZIP and vIRF1

Inhibition of extrinsic apoptotic signaling

vFLIP

The mitochondrial anti-apoptotic proteins: vBCL-2, vIAP

Conclusions

REFERENCES

31 Human gammaherpesvirus immune evasion strategies

Introduction

Immune system overview

Evasion of innate host immunity

Complement deregulation

Cytokine responses

Interleukin and chemokine responses

Interferon responses

Apoptosis responses

Natural killer (NK) cell responses

Evasion of other innate cellular responses

Evasion of adaptive host immunity

Evasion of CTL responses

Evasion of CD4+ T helper cell and B cell responses

Conclusions

REFERENCES

Part III Pathogenesis, clinical disease, host response, and epidemiology: alphaherpes viruses

32 Pathogenesis and disease

Pathogenesis

Unique biologic properties of HSV that influence pathogenesis

Pathology

Pathology of central nervous system disease

Impact of host response to infection on disease

Disease consequences

Orolabial infection

Primary infection

Reactivation

Genital infection

Primary infection

Reactivation

Keratoconjunctivitis

Cutaneous infections

Central nervous system infections

Neonatal infection

Infection in compromised hosts

Acknowledgment

REFERENCES

33 Molecular basis of HSV latency and reactivation

Introduction

Model systems to study latency

The latent genome

The latency-associated transcripts

Structure of LATs

The LAT promoter

Major LAT ORFs

Establishment of latency

A block to HSV IE transcription

Role of LAT in the establishment of latency

Alternative models for establishment of latency

Maintenance of latency

Reactivation

The role of ICP0 in reactivation

The ICP0 promoter as a possible target for reactivation signals

Cellular reactivation signals

The role of LAT in reactivation

Concluding remarks

Acknowledgments

REFERENCES

34 Immunobiology and host response

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

TCRgammaδ cells

Additional interactions between HSV and the immune system

Summary

REFERENCES

35 Immunopathological aspects of HSV infection

Introduction

Herpes infections and ocular disease

Keratitis in humans

Animal models for SK

Innate reactions to infection in the mouse model

Adaptive immunity in SK

Human Uveitis

The rabbit model for HSV uveitis

Acute retinal necrosis (ARN) in humans

The mouse model of ARN

Herpes simplex virus in the nervous system

Ganglionitis

Other possible HSV induced immune mediated conditions

REFERENCES

36 Persistence in the population: epidemiology, transmission

Epidemiology of HSV-1 and HSV-2

Spectrum of clinical disease

Immunocompetent host

Oral herpes

Genital herpes

Other mucocutaneous infections

HSV infection in CNS

Eye disease

Other syndromes

Neonatal herpes

Immunocompromised persons

Viral shedding

Transmission dynamics

Management and Prevention

Treatment

Treatment of recurrent mucocutaneous herpes

Suppression of mucocutaneous herpes

Reduction in transmission to sexual partners

Severe HSV infection

REFERENCES

Part III Pathogenesis, clinical disease, host response, and epidemiology: alphaherpes viruses VZV

37 VZV: pathogenesis and the disease consequences of primary infection

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)

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 car

VZV proteins have different activities in neurons than in permissive cells due to differences in cel

Future directions

REFERENCES

39 VZV immunobiology and host response

Immunobiology

Introduction

VZV encoded downmodulation of cell-surface MHC class I expression

VZV encoded inhibition of IFN gamma-mediated up-regulation of cell-surface MHC class II

VZV interference with the NF-kB pathway

VZV infection of human dendritic cells and transmission to T-cells

VZV encodes an immune evasion strategy during the productive infection of mature dendritic cells

The host immune response

Immunity during primary VZV infection

VZV immunity during latency

Persistence of VZV-specific memory

Immunity during VZV reactivation

REFERENCES

40 VSV: persistence in the population

Varicella: prevaccine epidemiology

Transmission

Periodicity and seasonality

Congenital (fetal) varicella syndrome

Incidence and seroprevalence

Age and climate

Urban/rural (risk of exposure)

Other factors: sex, race, number of siblings in the household and child care

Hospitalization and deaths

Varicella epidemiology: post-vaccine era

Herpes zoster epidemiology

Methodological issues

Seasonality and clustering

Secular trends

Dermatomal distribution

Incidence

Age

Sex

Race

Stress

Age of varicella infection

Exposure to varicella

Immunocompromising states

Complications

Hospitalizations

Deaths

Impact of vaccination

Herpes zoster in vaccinated children

Vaccination for prevention of herpes zoster

Acknowledgements

REFERENCES

Part III Pathogenesis, clinical disease, host response, and epidemiology: betaherpesviruses

41 Virus entry into host, establishment of infection, spread in host, mechanisms of tissue damage

Introduction

Acquisition of HCMV: Sources of virus and transmission within populations

Sources of HCMV in the community

Young children as a source of HCMV

Acquisition of HCMV by sexual contact

Sources of HCMV in hospitalized patients and health-care workers

Reinfection: acquisition of HCMV by a previously infected host

Entry and spread within susceptible hosts

Infection following community exposure

Transfusion and allograft-acquired infection

Spread within the host

Cell-associated spread within the host

Viral genes associated with virulence: viral dissemination and in vivo tropism

Disease and HCMV infection: pathogenesis of end-organ disease in acute infection

Disease and HCMV infection: pathogenesis of end-organ disease related to chronic infections

REFERENCES

42 Molecular basis of persistence and latency

Introduction

Sites of HCMV persistence and latency

ECs are a site of persistent HCMV replication

Determinants of EC tropism

Myeloid lineage cells are a site of HCMV latency

CD14+ monocytes and MDM

Growth of HCMV in Con A-MDM

Growth of HCMV in Allo-MDM

CD34+ hematopoietic and CD33+ GM-Ps

Determinants of myeloid lineage cell tropism

Role of apoptotic inhibitors in EC and MDM tropism

Summary

Acknowledgments

REFERENCES

43 Immunobiology and host response

Introduction

Cells of the immune system as sites of latency and reactivation for HCMV

The immune response to HCMV in the human host

Lessons from animal models of CMV disease

Antibody and complement

The HCMV specific CD8+ T-cell response

The HCMV-specific CD4+ T-cell response

HCMV, innate immunity and natural killer (NK) cells

The immune response and pathology in immunocompromised subjects

Immunosuppression by CMV

Immunopathology in human CMV disease CMV pneumonitis

CMV retinitis and immune recovery vitritis

CMV and inflammatory demyelinating neuropathy

CMV and organ transplant rejection

REFERENCES

44 Persistence in the population: epidemiology and transmisson

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 transmission

Congenital cytomegalovirus infection and the placenta

Congenital CMV infection

CMV infects specialized cells in the placenta

Placental development in early gestation

Diverse cell types in the uterus

Development of the hemochorial human placenta

Invasive cytotrophoblasts modulate the expression of stage-specific antigens

CMV infects the placenta in vitro and in utero

Potential routes for CMV transmission

CMV protein expression in placental cells in chorionic villi infected in vitro and in utero

Pathogenic microorganisms at the placental–decidual interface

Neutralizing antibodies to CMV gB in placental syncytiotrophoblasts

Patterns of CMV-infected-cell proteins in the decidua and placenta

Different patterns of CMV infection in the decidua mirrored in the adjacent placenta

Complexes of IgG and CMV virions transcytosed from maternal circulation across syncytiotrophoblasts

CMV infection dysregulates cytotrophoblast differentiation/invasion in vitro

CMV replicates in placental cytotrophoblasts in vitro

CMV infection in vitro downregulates cytotrophoblast expression of HLA-G

CMV infection in vitro downregulates alpha 1beta1 integrin expression and impairs cytotrophoblast in

CMV infection downregulates MMP activity altering cell-cell and cell–matrix interactions

CMV IL-10 dysregulates MMP activity

CMV IL-10 impairs endothelial cell migration and cytotrophoblast invasiveness in vitro

Concluding remarks

REFERENCES

Part III HHV-6A, 6B, and 7

46 HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease

Virus entry and establishment of infection

Cell tropism in vitro

Cell tropism in vivo

Entry

Envelope glycoproteins for entry process

Spread in host, mechanisms of tissue damage

Growth properties

Effects of virus infection on host cells

Disease consequences

Clinical features in hosts

Primary infection

Immune response during primary infection

Other symptoms associated with primary HHV-6 and 7 infection

Reactivation of HHV-6 and its clinical symptoms

Bone marrow transplantation (BMT)

Solid organ transplantation

AIDS

The other possible associated diseases

Multiple sclerosis (MS)

Drug hypersensitivity

REFERENCES

47 HHV-6A, 6B, and 7: molecular basis of latency and reactivation

Introduction

Latency-associated transcripts of HHV-6

Gene regulation of latency-associated transcripts

First molecular event of HHV-6 reactivation

Summary

REFERENCES

48 HHV-6A, 6B, and 7: immunobiology and host response

Introduction

Cell tropism

In vitro

In vivo

Antigens

HHV-6A and HHV-6B antigens

Latent antigens

Lytic antigens

Monoclonal antibodies (MAbs)

Targets of complement independent neutralization

Targets for diagnosis

HHV-7 antigens

HHV-7monoclonal antibodies

Targets for diagnosis

Immunologic cross-reactivity

HHV-6A and HHV-6B

HHV-6 and HHV-7

Roseoloviruses and other viruses

Immune response

Immune response after primary infection

Innate immune response

Antibody response

IgMantibodies

IgG antibodies

Neutralizing antibodies

T lymphocyte response

Possible role of reactivation

Immune responses in immunocompromised hosts

Allogeneic bonemarrow and blood stemcell transplantation

Solid organ transplantation

Multiple sclerosis (MS)

Virally mediated immune modulation

Cell surface markers

Effects on specific cell types

NK cells

Stemcells

T-lymphocytes

T-cell apoptosis

Proliferation

Dendritic cells

Histiocytes

Cytokine production

Virally encoded immune modulators

Other immune evasion mechanisms

Clinical significance of immunomodulation

Organ transplantation

HIV disease

Future directions

REFERENCES

49 HHV-6A, 6B, and 7: persistence in the population, epidemiology and transmission

Introduction

Persistence of HHV-6 and HHV-7 in individuals

Epidemiology of HHV-6 and HHV-7

HHV-6 variants A and B

HHV-6 and HHV-7 genotypes

HHV-6 integration

Transmission of HHV-6 and HHV-7

Concluding comments

REFERENCES

Part III Pathogenesis, clinical disease, host response, and epidemiology: gammaherpesviruses

50 Clinical and pathological aspects of EBV and KSHV infection

EBV

Infection in the normal host

Therapy

Infection in patients with congenital immunodeficiencies

Chronic active EBV

Infection in HIV patients

Other illnesses

EBV-associated tumors

Burkitt’s lymphoma

Post transplant lymphoproliferative disorders (PTLD)

AIDS lymphomas

Extranodal T/NK cell tumors

Nasopharyngeal carcinoma

Hodgkin’s lymphoma

Gastric cancers

Other EBV-associated tumors

Breast cancer, hepatocellular cancer, thymoma and other tumors

The clinical importance of the viral association

KSHV

Primary KSHV infection

KSHV-associated angioproliferative and lymphoproliferative disorders

Kaposi’s sarcoma

Treatment

Castleman’s disease and plasmablastic lymphomas

Primary effusion lymphoma and related lymphomas

Conclusions

REFERENCES

51 EBV: immunobiology and host response

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

Modulation of the cytokine network

Regulation of antigen processing and presentation

T-cell control of EBV-associated malignancies

Future prospects for an EBV vaccine

REFERENCES

52 Immunobiology and host response to KSHV infection

Introduction

Primary infection

Innate immunity

Dendritic cells

Natural killer cells

Complement

Adaptive immunity

T-lymphocytes

Cytotoxic T-lymphocytes

CTL epitopes

Effects of HAART on CTL

Helper T-lymphocytes

B-lymphocytes

Antibody epitopes and serological assays for anti-KSHV antibody detection

Effects of HAART on humoral responses

How antibodies contribute to KSHV immunity

FURTHER READING

Conclusions and future perspectives

REFERENCES

53 The epidemiology of EBV and its association with malignant disease

EPSTEIN-BARR VIRUS EPIDEMIOLOGY

Epidemiology of primary Epstein-Barr virus infection

Age at primary infection

Geographic variation

Sex differences

Socioeconomic factors

Genetic and racial factors

Transmission

EBV viral load epidemiology

Infectious mononucleosis

Epidemiology

Risk factors for infectious mononucleosis

EBV dynamics during infectious mononucleosis

Chronic active EBV infection

Epidemiology

X-linked lymphoproliferative syndrome

Epidemiology

Epstein–Barr virus and malignant neoplasms

Nasopharyngeal carcinoma

Epidemiology

Evidence of association with EBV

Tumors of the lymphoid tissues

Burkitt’s lymphoma/leukemia

NK/T-cell lymphomas

Hodgkin’s lymphoma

Lymphoproliferative disease associated with immunodeficiency

Gastric carcinoma

Epidemiology

Evidence of an association with EBV

Other malignancies associated with EBV infection

Lymphoepithelioma-like carcinomas

Leiomyosarcoma

Other malignancies

REFERENCES

54 The epidemiology of KSHV and its association with malignant disease

Introduction

Diagnosis of KSHV infection

Initial serologic assays for KSHV antibodies

Methodologic challenges in serologic assay development

Approaches using a combination of antibody assays

Recently developed eukaryotically derived recombinant antigen-based serologic assays

Seroreversion

Differential reactivity to KSHV antigens over time

Utility of currently available serologic assays

Epidemiology of KSHV infection

Prevalence of infection Geographic distribution

Temporal patterns

Genotypic diversity of infection

Routes of transmission

Transmission in non-endemic areas

Sexual transmission

Organ transplantation

Transmission in endemic areas

Non-sexual horizontal transmission

Sexual transmission

Vertical transmission

Blood transfusion

Disease manifestations

Primary infection syndrome

Kaposi’s sarcoma

Other diseases

Acknowledgments

REFERENCES

55 EBV-induced oncogenesis

Introduction

EBV infection in vivo

Characteristics of latent infection

DNA structure

EBV expression in latent infection

The EBNA proteins

Latent membrane protein 1

Latent membrane protein 2 (LMP2)

EBV-encoded RNAs (EBER)

BamHI A transcripts (BARTS)

Malignancies associated with EBV

Post-transplant lymphoproliferative disease

Burkitt’s lymphoma

Characteristics of EBV Infection in BL

Contributing factors

AIDS-associated lymphoma

Nasopharyngeal carcinoma

Characteristics of EBV infection in NPC

Contributing factors

Hodgkin’s lymphoma

T-cell lymphoma

Rare carcinomas

Contributing factors

Genetic factors

Tumor suppressor inactivation

EBV strain variation

Summary and future considerations

EBV-targeted therapy

REFERENCES

56 KSHV-induced oncogenesis

Primary effusion lymphoma (PEL)

The KSHV latency program in PEL

Latency-associated nuclear antigen (LANA)

v-cyclin

v-FLIP

K10.5/v-IRF3/LANA2

Kaposin

Latent KSHV miRNAs

Other KSHV genes and PEL

Multicentric Castleman’s disease (MCD)

Kaposi’s sarcoma

KSHV and KS: the big picture

KSHV gene expression in KS

Conclusions

REFERENCES

Part IV Non-human primate herpesviruses

57 Monkey B virus

Introduction

History

Distribution in nature

The virus

Isolation and growth properties of B virus

The B virus genome

Synthesis of viral proteins

Pathology and pathogenesis

The natural host

Experimental infections

Human infection

Latency

Epidemiology

Animals

Humans

Host immune responses

Clinical Manifestations of disease

Diagnosis

Non-human primates

Humans

Control of B virus infection

Conclusions

REFERENCES

58 Simian varicella virus

Introduction

Similarities between SVV and VZV

Simian varicella virus genome

SVV pathogenesis

Acknowledgments

REFERENCES

59 Primate betaherpesviruses

Natural history

Historical evidence of CMV in NHP

Seroprevalence

Infection in immunocompetent hosts

Pathogenesis

Viral dynamics of primary infection

Immunological parameters of primary infection

Virological and immunological parameters of chronic infection

Infection in non-immunocompetent hosts

Retroviral-induced immunodeficiency

Transplantation

Immunosuppression associated with measles virus

Fetal Infection

Molecular biology

Virion structure

Genome coding content

Genome structures

Gene arrangements

Genomic DNA sequences

Herpesvirus core proteins

Betaherpesvirus-specific proteins

Primate CMV-specific proteins

Summary

Acknowledgments

REFERENCES

60 Gammaherpesviruses of NewWorld primates

Introduction

Herpesvirus saimiri

Natural occurrence and pathology

Genome structure and replication

Immunomodulatory proteins

Oncogenesis

Growth transformation of human T-cells

Vectors for gene therapy

Herpesvirus ateles

Natural occurrence and pathology

Genome structure and replication

Oncogenesis

Lymphocryptoviruses of New World primates

Conclusions

Acknowledgments

REFERENCES

61 EBV and KSHV – related herpesviruses in non-human primates

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

Epstein–Barr virus nuclear antigen-1 (EBNA-1)

Epstein–Barr virus nuclear antigen-2 (EBNA-2)

Epstein–Barr virus nuclear antigen- 3A,3B,3C (EBNA-3A, 3B, 3C)

EBV latent membrane protein (LMP-1)

EBV latent membrane protein-2 (LMP-2)

Rhesus LCV as an animal model system for EBV

Other lymphocryptoviruses in Old World primates

Lymphocryptoviruses of New World monkeys

The marmoset LCV (CalHV3) genome

CalHV3 C1

CalHV3 ORF39 (EBNA-1)

CalHV3 C5

CalHV3 C7

New World primates as an animal model system for EBV

Evolution of New and Old World rhadinoviruses

Rhadinoviruses of Old World primates

Phylogenetic analysis

Retroperitoneal fibromatosis herpesviruses: RFHVMm and RFHVMn

Rhesus monkey rhadinovirus (RRV)

Genomic organization of RRV

RRV R1

RRV vIL6

RRV vGPCR

RRV Orf50/Rta and RRV R8

RRV LANA

RRV transcription program

RRV capsid structure

RRV pathogenesis

RRV as an animal model system for KSHV

Conclusions

Acknowledgments

REFERENCES

Part V Subversion of adaptive immunity

62 Herpesvirus evasion of T-cell immunity

Disruption of class I MHC antigen presentation

Interference with proteasomal proteolysis

Interference with peptide transport

Interference with ER chaperones required for class I biosynthesis

Destruction of class I molecules via proteasomal proteolysis

Disruption of the class I secretory pathway

Rerouting of class I molecules from the Golgi to the endolysosomal pathway

Retrieval of cell surface class I molecules

Interference with class I molecules at the cell surface

Interference with the immunological synapse

Interference with costimulation

Interference with APC function

Stunning of Cytotoxic T-cell activity

CTL escape mutants

Inhibition of T-cell receptor signaling

Erroneous T-cell activation

Disruption of class II MHC antigen presentation

Interference with class II expression

Manipulation of class II molecules

Conclusions

Acknowledgments

REFERENCES

63 Subversion of innate and adaptive immunity: immune evasion from antibody and complement

Role of the herpesvirus IgG Fc receptor in immune evasion

Introduction

IgG Fc receptors on mammalian cells

Herpes simplex virus FcgammaR

gE and gI structure

The HSV-1 FcgammaR and immune evasion

Human CMV FcgammaR

Varicella zoster FcgammaR

vFcgammaRs on non-human mammalian herpesviruses

Murine CMV

Pseudorabies virus

Summary of vFcgammaR studies

Role of the herpesvirus complement receptors in immune evasion

Introduction

Regulation of complement

Strategies employed by human herpesviruses to evade complement immunity

Viral proteins homologous to human complement regulatory proteins: Kaposi’s sarcoma associated her

Viral proteins with no sequence homology, yet functional similarities with human complement regulato

HSV-1 and HSV-2 glycoprotein gC

EBV complement regulatory activity: unidentified protein

Viruses that incorporate human complement regulatory proteins into their envelope during viral matur

Strategies employed by non-human mammalian herpesviruses to evade complement immunity

Viral proteins homologous to mammalian complement regulatory proteins

Murine Gammaherpesvirus 68: MHV-68 RCA

Herpesvirus saimiri (HVS): complement control protein homologue (CCPH)

HVS: CD59

Viral proteins with no sequence homology, yet functional similarities with mammalian complement regu

Summary of viral complement regulatory proteins

REFERENCES

Part VI Antiviral therapy

64 Antiviral therapy of HSV-1 and -2

Introduction

First-line antiviral agents for HSV-1 and HSV-2 infections

Acyclovir

Mechanism of action and pharmacokinetics

Antiviral therapy

Clinical efficacy inHSV-1 and HSV-2 infections

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Antiviral resistance

Famciclovir/penciclovir

Mechanism of action and pharmacokinetics

Antiviral therapy

Clinical efficacy in HSV-1 and HSV-2 infections

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Dosage regimens

Antiviral resistance

Valaciclovir

Mechanism of action and pharmacokinetics

Antiviral therapy

Clinical efficacy inHSV-1 and HSV-2 infections

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Dosage regimens

Antiviral resistance

Second-line antiviral agents for HSV-1 and HSV-2 infections cidofovir

Mechanism of action and pharmacokinetics

Antiviral therapy

Clinical efficacy inHSV-1 and HSV-2 infections

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Dosage regimens

Foscarnet

Mechanism of action and pharmacokinetics

Antiviral therapy

Clinical efficacy in HSV-1 and HSV-2 infections

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Dosage regimens

Antiviral resistance

Ganciclovir

Mechanism of action and pharmacokinetics

Antiviral therapy

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Dosage regimens

Antiviral resistance

Valganciclovir

Mechanism of action and pharmacokinetics

Antiviral therapy

Challenges for achieving clinical benefit, including adverse drug effects

Clinical indications

Dosage regimens

Antiviral resistance

REFERENCES

65 Antiviral therapy of varicella-zoster virus infections

Introduction

Diagnosis

Drugs with activity against VZV

Acyclovir and valacyclovir

Penciclovir and famciclovir

Other drugs

Brivudin

Foscarnet

Vidarabine

Interferon

Clinical indications for therapy

Varicella

Children

Adults

Pregnant women

Immunocompromised patients

Patients with HIV infection

Herpes zoster

Immunocompetent adults

Herpes zoster ophthalmicus

Immunocompromised patients

HIV-seropositive patients

Clinical indications for prophylaxis

Varicella

Immunocompetent patients

Pregnant women

Immunocompromised (including HIV-seropositive) patients

Herpes zoster

Immunocompetent patients

Immunocompromised patients

HIV-seropositive patients

Drug-resistant varicella-zoster virus

REFERENCES

66 Antiviral therapy for human cytomegalovirus

Introduction

Licensed drugs and mechanism of action

Nucleosides

Nucleotides

Foscarnet

Fomivirsen

Clinical efficacy; challenges for achieving clinical benefit

Pathogenesis

Viremia and viral load

Disease processes within infected organs

Direct effects

Indirect effects

Clinical manifestations of CMV end-organ disease

Fever/leukopenia

Hepatitis

Gastrointestinal disease

Retinitis

Encephalitis

Polyradiculopathy

Pneumonitis

Hearing loss

Laboratory diagnosis

Detection of viremia

CNS involvement

DEAFF/Shell vial

Histopathology

Cell culture

Serology

Clinical indications for antiviral prophylaxis and dosage regimens

Management

Strategies for deploying antiviral agents

True prophylaxis

Delayed prophylaxis

Suppression

Pre-emptive therapy

Treatment of established disease

Results of double-blind, randomized, placebo-controlled trials

Aspects of CMV management in HIV-infected individuals

Conclusions

Resistance

Methods used to define resistance

Gene UL 97

Gene UL54 (DNA polymerase)

Patterns of cross-resistance

Recognition of resistance in clinical practice

REFERENCES

67 New approaches to antiviral drug discovery (genomics/proteomics)

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 resistance

The drug development process: an overview

Host cell targets as an approach to virus inhibition

Antiviral targets in early replication events

PD146626

Non-nucleoside pyrrolopyrimidines 828, 951, and 1028

CMV423

ISIS 13312

Antiviral targets in the herpesvirus DNA replication complex

Herpesvirus DNA polymerase inhibitors

Nucleoside/nucleotide analogue inhibitors

Non-nucleotide inhibitors

Herpes helicase-primase inhibitors

Inhibitors of DNA processing and packaging

Inhibitors of the portal protein of HSV

WAY 150138

Comp I

Dihydroxyacridone series

Inhibitors of the CMV terminase complex

TCRB and BDCRB

GW275175X

BAY 38–4766

Protease inhibitors

Inhibitors of the CMV UL97 encoded protein kinase

Indolocarbazoles

Maribavir

Antivirals with activity against EBV, HHV-6, HHV-7, and HHV-8

Conclusions

REFERENCES

Part VII Vaccines and immunotherapy

69 Herpes simplex vaccines

Introduction

History of HSV vaccine development

Development of live, attenuated vaccines

Subunit vaccines

Other approaches to vaccination

Conclusions

REFERENCES

70 Varicella-zoster vaccine

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 vaccines

Cytomegalovirus and human disease

The case for a cytomegalovirus vaccine

Natural immunity confers protection

Immunology of HCMV protection

Vaccine development

Replicating vaccines

Subunit vaccines

Vectored vaccines

Peptide vaccines

DNA vaccines

Subviral particles

Challenges for HCMV vaccine development

Species-specificity of HCMV

Efficacy testing

When to vaccinate

Summary

REFERENCES

72 Epstein–Barr virus vaccines

Introduction

Vaccines to prevent infectious mononucleosis

Gp350

EBNA3

Vaccines to prevent post-transplant lymphoproliferation disease

Therapeutic vaccines to prevent Hodgkin’s disease and nasopharygeal carcinoma

LMP polyepitope vaccines

Altered antigen processing of LMPs using bacterial toxins

Therapeutic vaccines for Burkitt’s lymphoma

Conclusions

REFERENCES

73 DNA vaccines for human herpesviruses

General design of DNA vaccines

Mechanism of action

DNA vaccines: advantages and disadvantages

Features of pDNA constructs especially conducive to herpesvirus vaccine development

Animal and human experience with DNA vaccines

Improving DNA vaccine potency

DNA vaccines for specific human herpesviruses Cytomegalovirus

Genes of interest

Animal studies

Human trials

Herpes simplex virus 1 and 2

Genes of interest

Animal studies

Human trials

Varicella-zoster virus

Genes of interest

Animal studies

Human trials

Epstein–Barr virus

Genes of interest

Animal studies

Human trials

Summary

REFERENCES

74 Adoptive immunotherapy for herpesviruses

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

Clones vs. polyclonal lines

Antigen

APC

Selection of specific T-cells

CTL expansion

Regulation

Conclusions and future considerations

REFERENCES

75 Immunotherapy of HSV infections – antibody delivery

Immune responses following HSV infection

Neonates

Human studies suggesting of protection by HSV antibodies

Adults

Neonates

Animal models of antibody immunotherapy in HSV infection and disease

Limitations of antibody immunotherapy

Summary

REFERENCES

Part VIII Herpesviruses as Therapeutic Agents

76 Herpesviruses as therapeutic agents

Introduction

Properties of therapeutic HSV vectors

Properties of non-replicating HSV vectors for therapeutic use

Plasmid-based amplicon vectors

Replication defective whole genome vectors

Use of HSV vectors to modify the nervous system

Peripheral nervous system (PNS)

Central nervous system (CNS)

Malignant glioma

Towards optimizing HSV vectors for therapeutic use

Non-replicating vectors: current trends

Oncolytic HSV

Introduction

Oncolytic HSV in malignant glioma

Oncolytic HSV for Non-CNS malignancies

HSV1716: melanoma

NV1020: colorectal metastases

HSV and other cancers

Oncolytic HSV: current directions

REFERENCES

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Tags: Ann Arvin, Gabriella Campadelli Fiume, Edward Mocarski, Patrick S Moore, Bernard Roizman, Richard Whitley, Koichi Yamanishi, Human, Herpesviruses, Biology