Varicella-zoster Virus (eBook)

Preface 6
Contents 8
The Varicella-Zoster Virus Genome 16
1 Genome Structure and Organization 17
1.1 VZV Genome 17
1.2 VZV Genes 18
1.2.1 VZV Immediate-Early Genes 18
1.2.2 VZV Genes Encoding Replication Proteins 18
1.2.3 VZV Genes Encoding Putative Late Proteins 20
1.2.4 VZV Genes Encoding Glycoproteins 20
2 Comparative Genomics of VZV and HSV 21
2.1 Core Proteins Conserved with Herpesviruses in Other Subfamilies 21
2.2 VZV Functional and Nonfunctional Homologs of HSV Genes 21
2.3 VZV Genes Not Conserved with HSV 21
2.4 HSV Genes Not Conserved with VZV 22
3 Mutagenesis with Cosmids and BACs 22
3.1 Mutagenesis Using Marker Rescue 22
3.2 Mutagenesis Using Cosmids 22
3.3 Mutagenesis Using BACs 23
3.4 Results of Mutagenesis Studies 23
3.5 VZV as an Expression Vector 25
3.6 Use of Genetics to Develop Safer VZV Vaccines 26
References 26
VZV Molecular Epidemiology 30
1 Introduction 31
1.1 What is Molecular Epidemiology? 31
1.2 VZV Molecular Epidemiology: The Historical Context 31
2 Genetic Variation in VZV: Tools for Molecular Epidemiology 32
2.1 Restriction Fragment Length Polymorphisms 32
2.2 Length Polymorphisms of Variable Regions 34
2.3 Restriction Site Polymorphisms: BglI and PstI Digests 35
2.4 Single Nucleotide Polymorphisms 36
2.5 Genome Sequencing 41
3 Molecular Epidemiology in Practice 41
3.1 Varicella-Zoster Virus Evolution and Clades 41
3.1.1 Mutation and Evolution of VZV 42
3.1.2 Recombination and VZV Evolution 43
3.1.3 Reconstructing the Evolutionary History of VZV 43
3.2 Geographical Spread of VZV Strains 44
3.3 Molecular Epidemiology and VZV Pathogenesis 47
3.3.1 Genotyping, Reinfection, and Reactivation 47
3.3.2 Genotyping and Virulence 48
3.4 Molecular Epidemiology Transmission and Infection Control 49
3.5 Molecular Epidemiology of VZV Outbreaks 50
3.5.1 Molecular Epidemiology and Public Health 51
4 Summary 52
References 52
Roles of Cellular Transcription Factors in VZV Replication 58
1 Introduction 59
2 Role of the Eukaryotic Mediator Complex in IE62-Directed Transcriptional Activation 60
2.1 Mediator 61
2.2 Physical and Functional Interaction Between Mediator and IE62 62
2.3 Mapping of the Minimal IE62 TAD 64
2.4 The IE62 TAD Interacts Directly with MED25 64
2.5 The IE62 TAD Is Unstructured in the Absence of a Binding Partner 65
2.6 Future Directions 66
3 Mechanisms of Activation of the ORF62 Promoter 67
3.1 HCF-1 67
3.2 HCF-1 and Chromatin Remodeling 68
3.3 Future Directions 69
4 Cellular Transcription Factors and Origin-Dependent DNA Replication 70
4.1 Interaction of Transcription Factors with the Downstream Region of oriS 72
4.2 The Sp1/Sp3 Site Is Involved in Origin-Dependent DNA Replication 73
4.3 Future Directions 73
5 Summary 74
References 74
Effects of Varicella-Zoster Virus on Cell Cycle Regulatory Pathways 81
1 Introduction 82
1.1 VZV Tropism for Nondividing Cells 82
1.2 Characterization of the Cell Cycle in VZV Host Cells 83
1.3 VZV Dysregulates the Cell Cycle in Human Foreskin Fibroblasts 85
1.4 Virus and Host DNA Synthesis in VZV-Infected Human Foreskin Fibroblasts 86
1.5 Concluding Remarks 89
References 89
Varicella-Zoster Virus Open Reading Frame 66 Protein Kinase and Its Relationship to Alphaherpesvirus US3 Kinases 92
1 Introduction 93
2 Genetics 93
3 ORF66 Structure and Characteristics 94
4 ORF66 Targets 96
4.1 Autophosphorylation 96
4.2 IE62 98
4.3 Matrin 3 99
4.4 Histone Deacetylases 100
5 Cellular and Viral Activities Modulated by the ORF66 Protein Kinase 101
5.1 MHC-I Surface Presentation 101
5.2 IFN Signaling 102
5.3 Apoptosis 103
6 Alphaherpesvirus US3 Kinase Studies that Guide the Search for Roles of ORF66 103
6.1 US3 Kinases and Inhibition of Apoptosis 104
6.2 US3 Modulation of HDAC 104
6.3 Nucleocapsid Egress 105
6.4 Alteration of the Host Cytoskeleton 106
7 Concluding Remarks 107
References 107
VZV ORF47 Serine Protein Kinase and Its Viral Substrates 112
1 Introduction 113
2 Molecular Evolution of VZV and ORF47 113
3 Kinase Activity of ORF47 Protein 114
4 Expression of a Cloned VZV ORF47 Gene 114
5 Autophosphorylation of ORF47 Protein 116
6 Phosphorylation of VZV IE62: The Major Transactivator 117
7 Phosphorylation of VZV IE63: A Latency-Associated Protein 117
8 Phosphorylation of VZV gE and gE Endocytosis 118
9 ORF47 and the Role of VZV gE in Cell-to-Cell Spread 119
9.1 Deduction of the ORF47 Kinase Consensus Sequence 121
References 122
Overview of Varicella-Zoster Virus Glycoproteins gC, gH and gL 125
1 Introduction 126
2 VZV gC Protein Structure 126
3 Delayed Expression of VZV gC Protein in Cultured Cells 128
4 Delayed VZV gC Transcription in Cultured Cells 130
5 Role of gC in Low VZV Infectivity 131
6 VZV gC and gH Proteins in Human Zoster Vesicles 132
7 VZV gH and gL Structure 133
8 Interaction and Trafficking of the VZV gH/gL Complex 133
9 Fusion Mediated by VZV gH and gL Coexpression 134
10 Endocytosis-Dependent Regulation of VZV gH-Mediated Fusion 136
11 VZV gH Neutralization Epitope 136
References 138
Analysis of the Functions of Glycoproteins E and I and Their Promoters During VZV Replication In Vitro and in Skin and T-Cell Xenografts in the SCID Mouse Model of VZV Pathogenesis 141
1 Introduction 142
2 gE Functions 144
3 gE Promoter Functions 154
4 gI Functions 154
5 gI Promoter Functions 156
6 Summary 156
References 157
Varicella-Zoster Virus Glycoprotein M 159
1 Introduction 160
2 VZV gM Is an Envelope Glycoprotein Modified with a Complex N-Linked Oligosaccharide 161
3 The Main Location of the gM in VZV-Infected Cells Is the trans-Golgi Network 162
4 VZV gM Plays a Role in the Cell-to-Cell Spread of Virus 162
5 Alternative Splicing of the VZV ORF50 Gene 165
References 165
Varicella Zoster Virus Immune Evasion Strategies 167
1 Introduction 168
2 VZV Interference with Interferons 169
3 Interference with Antigen Presentation by VZV 171
3.1 Downregulation of MHC Class I Molecules by VZV 171
3.2 VZV Interference with MHC Class II Expression 173
4 VZV Interference with the NFkappaB Pathway and Intercellular Adhesion Molecule 1 Expression 175
5 Impact of VZV on Human dendritic cells 176
6 Concluding Remarks and Future Perspectives 180
References 180
VZV Infection of Keratinocytes: Production of Cell-Free Infectious Virions In Vivo 184
1 Introduction 185
References 195
Varicella-Zoster Virus T Cell Tropism and the Pathogenesis of Skin Infection 200
1 Introduction 201
2 Defining Determinants of VZV Tropism for T cells and Skin in the SCID Model In Vivo 208
3 The Role of VZV Glycoproteins in T cell and Skin Infection 210
4 Conclusion 217
References 218
Experimental Models to Study Varicella-Zoster Virus Infection of Neurons 221
1 Introduction 222
2 Experimental VZV Infection of Primary Human Neurons from Dissociated Neural Tissue 222
2.1 Modulation of Neuronal Apoptosis by VZV 224
3 Models of Latent Infection of Human Neurons 225
4 Experimental VZV Infection of Intact Ganglia 226
5 VZV Infection of Neuronal Cell Lines 228
6 VZV Infection of Rodent Neurons 229
7 VZV Infection of Ganglionic Satellite Cells 231
8 Conclusions and Perspectives 232
References 233
Molecular Characterization of Varicella Zoster Virus in Latently Infected Human Ganglia: Physical State and Abundance of VZV DNA 239
1 Introduction 240
2 Ganglionic Cell Type Infected by VZV 241
3 Distribution of VZV DNA in Ganglia 241
4 Latent VZV Burden 241
5 Configuration of Latent VZV DNA 242
6 Epigenetic Regulation of Latent VZV Gene Transcription 242
7 The VZV Transcriptome 243
8 Detection and Quantitation of Individual VZV Transcripts in Latently Infected Ganglia 244
9 Development of a Novel Assay to Study VZV Gene Expression During Latency 244
10 MicroRNA Expression in Latently Infected Ganglia 248
11 VZV Protein in Latently Infected Ganglia 248
12 Future Directions 248
References 250
Neurological Disease Produced by Varicella Zoster Virus Reactivation Without Rash 252
1 Introduction 253
2 Zoster Sine Herpete 254
3 Preherpetic Neuralgia 255
4 Meningitis/Meningoencephalitis 255
5 Ramsay Hunt Syndrome 255
6 Polyneuritis Cranialis 256
7 Cerebellitis 256
8 Vasculopathy 257
9 Myelopathy 257
10 Ocular Disorders 257
11 Remarkable Cases of VZV Infection Without Rash 258
12 Systemic Disease Produced by VZV Reactivation Without Rash 258
13 Subclinical VZV Reactivation 259
14 Diagnostic Testing 259
References 260
Varicella-Zoster Virus Neurotropism in SCID Mouse-Human Dorsal Root Ganglia Xenografts 263
1 Introduction 264
2 The SCID Mouse-Human Xenograft Model for VZV Pathogenesis 265
3 SCID Mouse-Human DRG Xenografts 266
3.1 Xenotransplantation of Human DRG in SCID Mice 266
4 VZV Neurotropism in Human DRG Xenografts 268
4.1 Acute VZV Replication in Human DRG 268
4.2 Acute VZV Infection of Human DRG Xenografts Is Associated with Polykaryon Formation 269
4.3 Longterm Persistence of VZV in Human DRG Xenografts Following Acute Infection 271
4.4 Viral Genomic DNA Burden in DRG Xenografts Persistently Infected with VZV 273
4.5 Differential Regulation of Viral Gene Expression During VZV Persistence in Human DRG Xenografts 273
4.6 Expression of Viral Proteins During VZV Persistence in Human DRG Xenografts 274
4.7 Evaluation of DRG Xenografts as a System for Assessment of Antiviral Drugs 275
4.8 A Role for Innate Immunity During VZV Infection of DRG Xenografts 275
4.9 VZV T Lymphotropism May Facilitate Neurotropism 276
4.10 VZV ``Oka´´ Varicella Vaccines Retain Neurotropism 277
5 Investigation of VZV Neurovirulence Using Recombinant VZV Mutants 277
5.1 Generation of VZV Recombinants 277
5.2 The Role of Glycoprotein I in VZV Neurotropism 278
5.3 Effect of Targeted Mutation of gI Promoter Elements on VZV Neurotropism 280
6 Conclusion 281
References 281
Rodent Models of Varicella-Zoster Virus Neurotropism 285
1 Varicella-Zoster Virus Latency in Humans 286
2 VZV Latency in Rats 286
2.1 VZV Latency in Newborn Rats and Other Rodents 287
2.2 VZV Allodynia Model in Rats 287
3 VZV Transcripts in Latently Infected Rats and Cotton Rats 288
4 VZV Proteins in Latently Infected Rats 289
5 VZV Genes Important for Latency in Rats and Cotton Rats 290
5.1 Role of VZV Genes Not Conserved with HSV in Establishment of Latency in Rodents 290
5.2 Role of VZV Genes Expressed During Latency in Humans in Establishment of Latency in Rodents 291
5.3 Role of Other VZV Genes in Establishment of Latency in Rodents 292
5.4 Summary of Latency Studies in Rodents 293
6 Advantages and Limitations of the Rodent Model of VZV Latency 293
References 294
Simian Varicella Virus: Molecular Virology 298
1 Introduction 299
2 Cell-Associated Nature of SVV 299
3 SVV Morphology and Relatedness of SVV and VZV 300
4 The SVV Genome 301
5 SVV Gene Expression 308
6 Genetic Manipulation of the SVV Genome-SVV Mutants and Recombinant Viruses 310
References 312
Simian Varicella Virus Pathogenesis 316
1 Introduction 317
2 Animal Models of VZV Infection 317
3 Simian Varicella Virus 319
3.1 Clinical and Pathological Features 320
3.2 Immunological Features 320
3.3 Virological Features 320
3.4 Features of Latency and Reactivation 321
4 Experimental SVV Infection 321
4.1 Model 1: Persistent Viremia 322
4.2 Model 2: Latency 322
4.3 Model 3: Latency and Reactivation 324
5 Conclusions 325
References 325
Varicella-Zoster Virus Vaccine: Molecular Genetics 329
1 Introduction 330
1.1 Development of Varicella Vaccine 330
1.2 Prevention of Varicella in the United States 330
2 Genetic Markers in the Vaccine 331
2.1 Vaccine-Associated Single Nucleotide Polymorphisms 331
2.2 Insights from Vaccine Adverse Event Isolates 333
2.3 Composition of Commercial Varicella Vaccine Preparations 335
3 Discrimination of Oka Vaccine from Wild-Type Strains 336
3.1 Overview 336
3.2 PCR Methods for Discriminating Vaccine from Wild Type 337
3.3 Impact of Changing VZV Epidemiology 338
3.4 Specimen Collection 339
3.5 The Role of Recombination in Varicella Vaccine Surveillance 340
4 Summary 341
References 342
VZV T Cell-Mediated Immunity 347
1 Introduction 348
2 VZV-Specific T Cell Immunity Acquired from Wild Type VZV Infection 349
2.1 Characteristics of VZV-Specific T Cell-Mediated Immunity 349
2.2 Kinetics of VZV-Specific T Cell-Mediated Immunity After Varicella 350
2.3 Kinetics of VZV-Specific T Cell-Mediated Immunity After Herpes Zoster 351
2.4 Effect of Age on VZV-Specific T Cell-Mediated Immunity 351
2.5 Clinical Evidence of Protection Against Varicella Conferred by VZV-Specific T Cell Mediated Immunity 353
2.6 Clinical Evidence of Protection Against HZ Conferred by VZV-Specific T Cell Mediated Immunity 354
3 VZV-Specific T Cell Immunity Acquired from Vaccination 355
3.1 Varicella Vaccine 355
3.2 Herpes Zoster Vaccine 356
3.3 Forward-Looking Statement 359
References 360
Perspectives on Vaccines Against Varicella-Zoster Virus Infections 364
1 Varicella-Zoster Virus 365
2 Varicella Vaccine 366
3 Vaccine Safety 368
4 Effectiveness of Varicella Vaccine 370
5 Vaccination Against Zoster 373
References 374
Index 378