Human Herpesvirus-6 (eBook)

Cover 1
Contents 8
Foreword by Robert Gallo 12
Foreword by Ronald Glaser and Marshall Williams 14
Preface 16
Part I: General Virology 18
Discovery and Classification of Human Herpesvirus-6 (HHV-6) 20
Discovery 20
Nomenclature and classification 24
References 27
Ultrastructure and Assembly of Human Herpesvirus-6 (HHV-6) 28
Introduction 28
Herpesvirus-6 assembly and maturation 30
Three-dimensional structure of HHV-6 capsid 33
Comparision of the HHV-6 cappsid structure with those of other human herpesviruses 35
Conclusion 36
References 36
HHV-6 Genome: Similar and Different 40
Genome classification and biology 40
Genomes, cellular tropism and laboratory culture 41
Genome structure and repetitive sequence 43
Genome rearrangements and relationship to other herpesviruses 46
Genome composition and general molecular biology 46
Herpesvirus conserved and HHV-6-specific genes 55
Genomes and HHV-6 strains 56
Acknowledgements 60
References 60
Proteins of HHV-6 64
Introduction 64
IE proteins 64
U16/U17 66
U53, proteinase 67
U69, kinase 67
Cellular homologues 67
U94, AAV-2 rep homologue 68
Envelope glycoproteins 69
U39, gB 69
U48 and U82, gH and gL 70
U100, gQ 70
U47, gO 71
U11 71
U14 71
U27 72
Perspective 72
References 72
Biological Features of HHV-6 76
Introduction 76
HHV-6 cellular receptor 77
Species specificity 78
Cellular tropism of HHV-6 79
Target cells in vitro 79
Cellular and tissue host range in vivo 82
Biological effects of HHV-6 on the host cell 82
Cytopathic effects 82
Latent infection 83
Cellular transformation 84
Immune modulation 84
Human lymphoid tissue ex vivo: a new model for the study of HHV-6 pathogenesis 87
Dysregulation of complement activation 88
References 88
Part II: Diagnosis and Epidemiology 94
Strain Variants of HHV-6 96
Introduction 96
Epidemiology 98
Molecular biology 98
Biological aspects of variants A and B 99
Reactivity of monoclonal antibodies to HHV-6 variants A and B 100
Disease associations of HHV-6A and -6B variants 101
Roseola infantum 101
CNS disease 101
Epilepsy and HHV-6B 102
Transplantation and HHV-6 variants 102
HHV-6 (variants A and B) and multiple sclerosis 103
HHV-6A and chronic fatigue syndrome (CFS) 103
Concluding remarks 104
References 104
Serologic Testing for Acute and Chronic Infection 108
Introduction 108
Serologic assays 109
Techniques 109
Immunofluorescence assays 109
Enzyme immunoassays 110
Neutralization assays 111
HHV-6 antigens involved in serologic testing 111
Characterization of HHV-6-specific antibodies 112
Serologic findings 113
Seroprevalence studies 113
Primary infection 114
Latent infection and reactivations 115
Central nervous system diseases 115
Pending questions and perspectives 116
Acknowledgments 117
References 118
Molecular Testing for HHV-6 Infection 122
Introduction 122
Primary infection: characteristics and diagnostic considerations 123
PCR analysis of cell-free body fluids 124
Reverse transcription PCR analysis 124
Quantitative PCR analysis of HHV-6 DNA in PBMC or blood 125
Detection of virus variants 126
Other assay approaches 126
Future assay methods 126
PCR-based assays: general considerations and molecular underpinnings 128
Commercially available tests 129
General considerations for current molecular assays 129
References 130
Epidemiology of HHV6 136
The epidemiology of roseola from historical observations 136
Seroepidemiologic studies of HHV6 infection 137
Acquisition of HHV6 infection during childhood 137
Acquisition of HHV6 infection according to variant 138
Factors affecting acquisition of HHV6 infection 140
Mode of transmission 140
Postnatal infection 140
Congenital infection 141
Incubation period 142
Summary 143
References 143
Part III: Clinical Pathology 148
Pathologic Features of HHV-6 Disease 150
Introduction 150
Cell and tissue tropism and strain differences 151
General cellular pathology of HHV-6 infection 152
Primary infection 152
Reactivation and endogenous reinfection 156
Lymphatic and hematopoietic system (see also chapters 14 and 15) 158
Central nervous system (see also chapter 16) 159
Cardiovascular system (see also chapter 17) 159
Other organs and tissues (see also chapters 13 and 18) 160
Conclusions 160
References 160
Systemic Reactions to HHV-6 Infection 166
Introduction 166
From the anticonvulsant hypersensitivity syndrome to the DRESS 167
Clinical spectrum and systemic manifestations 168
DRESS and HHV-6: the first reports 169
HHV-6 reactivation in DRESS: ‘‘innocent bystander’’ or causal agent of systemic symptoms 171
HHV-6: a helper virus for other herpesviruses in DRESS? 173
Pathophysiology of HHV-6 reactivation in DRESS 175
Therapeutic implications 176
Conclusion 177
References 177
HHV-6 and the Integument 180
Introduction 180
Exanthem subitum 181
Skin rash and HHV-6 reactivation in hematopoietic stem cell transplant recipient 182
Drug-induced hypersensitivity syndrome and HHV-6 184
Pityriasis rosea and HHV-6 185
Pathogenesis of skin manifestations due to HHV-6 infection 185
References 187
HHV-6 and the Respiratory System 190
Introduction 190
Primary HHV-6 infection and the respiratory tract 191
Clinical features of primary HHV-6 infection in children 191
Pharynx, tonsils, eyes and ears 191
Upper respiratory tract 193
Lower respiratory tract 194
Non-primary HHV-6 infection and the respiratory tract 195
Interstitial pneumonia in not overtly immunocompromised persons 196
Pneumonitis in immunosuppressed patients 196
Resume 198
Acknowledgment 198
References 198
HHV-6 and the Lympho-Hematopoietic System 202
Introduction 202
In vitro data 203
Evolution of techniques used and evolution of findings 203
HHV-6 infection can induce atypical lymphoproliferations 204
The main LD associated with HHV-6, in immunocompetent subjects, is probably HD 207
Characteristics of HHV-6 found in lymph nodes 207
Viral quantification 207
HHV-6B is more often detected than HHV-6A 208
HHV-6 is found essentially in scleronodular HD in young adults 208
HHV-6 may be associated with EBV 209
HHV-6 is present in different cell types and also in RS cells 209
HHV-6 can also be detected in other lymphoproliferative diseases 209
NHL in immunocompetent subjects 210
B-cell lymphomas 210
T-cell lymphomas 210
Cerebral lymphomas and lymphomas with a predilection for the nervous system 211
Lymphomas in SS patients 211
HHV-6-associated lymphomas in immunocompromised individuals 211
Post-transplant LD 211
AIDS-related LD 211
Acute lymphoblastic leukaemia 212
Different mechanisms have been proposed for HHV-6 in lymphoproliferative diseases 212
HHV-6 exhibits transforming capacities 212
HHV-6 retains p53 within the cytoplasm 213
HHV-6 can transactivate genes 213
Transactivation of human genes 213
Transactivation of viral genes 214
EBV transactivation 214
HHV-8 transactivation 214
HHV-6 has the ability to integrate into host cell chromosomal DNA 214
HHV-6 may exert a role in cell proliferation by dysregulation of cytokine network 215
Conclusion 215
References 215
Human Herpesvirus-6 and the Cellular Immune System 218
Introduction 219
Isolation history: association with immunodeficiency disorders 219
Subversion of the immune system 219
In vitro studies: Th1 to Th2 switch
Reactivation: transplantation 221
Solid organ transplant 221
Bone marrow transplant 222
Current immunological tools 223
Disease associations between HHV-6 infection and multiple sclerosis, fibromyalgia, and chronic fatigue syndrome 224
Method: rapid immune function assay 224
Results: comparing healthy adults, stable transplant patients, HIV-infected patients, and CFS patients 224
Discussion and conclusions 226
References 227
HHV-6 and the Central Nervous System 230
HHV-6 infection of the central nervous system 230
HHV-6 in seizure disorders 231
The association of HHV-6 with MS 232
HHV-6 and PML 236
Acknowledgments 237
References 237
HHV-6 and the Cardiovascular System 242
Introduction 242
Case report 243
Discussion 247
References 249
HHV-6 in Cardiovascular Pathology 250
Introduction 250
Diseases of blood vessels 251
Diseases of the heart 253
Conclusions 256
References 256
HHV-6, the Liver and the Gastrointestinal Tract 260
Introduction 260
HHV-6 and hepatitis 260
HHV-6 association with other liver disease 262
Pathogenesis of HHV-6-associated hepatitis 263
HHV-6 and gastrointestinal tract 264
References 265
HHV-6 in Chronic Fatigue Syndrome 268
Chronic fatigue syndrome 268
Immune dysfunction 269
Viral implication 270
Proposed pathogenic model of CFS 270
Identifying subsets among the CFS population 271
HHV-6 association with CFS 271
HHV-6 in CNS of CFS patients 273
HHV-6 therapy in CFS patients 275
Immunomodulatory therapy for HHV-6 in CFS patients 276
HHV-6 diagnostic testing in CFS patients 276
Future research 277
Summary 277
References 278
HHV-6 and HIV-1 Infection 280
Introduction 280
In vitro interactions between HHV-6 and HIV-1 281
Productive coinfection of CD4+ T cells by HHV-6 and HIV-1 282
HIV-1 LTR transactivation by HHV-6 283
Effects of HIV-1 on HHV-6 replication 283
Direct virion– virion interactions 284
De nova induction of CD4 expression 284
Induction of inflammatory cytokines that modulate HIV replication 285
Mechanisms of direct immunological damage by HHV-6 285
In vivo studies of HHV-6 infection in HIV-1 disease 286
HHV-6 as an opportunistic agent in AIDS 287
Correlation between HHV-6 replication and HIV-1 disease progression 287
Experimental coinfection models ex vivo and in vivo 288
Coinfection studies in structurally intact human lymphoid tissue ex vivo: does HHV-6 favor the phenotypic switch of HIV-1? 288
In vivo coinfection with HHV-6 and HIV-1 in chimeric SCID-hu Thy/Liv mice: lack of reciprocal modulation 289
In vivo coinfection with HHV-6 and SIV in pig-tailed macaques (Macaca nemestrina): accelerated immunological and clinical progression to AIDS 289
Concluding remarks 291
References 291
Human Herpesvirus-6 Infection in Solid Organ and Stem Cell Transplant Recipients 296
Epidemiology 296
Transmission 297
Documented infections 297
Solid organ transplant recipients 297
Stem cell transplant recipients 298
Clinical manifestations 298
Indirect sequelae 301
Prevention and therapy 303
Acknowledgment 304
References 304
Therapeutic Approaches to HHV-6 Infection 308
Introduction 308
Antiviral assays for HHV-6 308
Classical viral DNA polymerase inhibitors 310
Mechanism of action 310
In vitro data 310
Clinical data 312
Antiviral studies in MS patients 313
New nucleoside analogs 314
New targets for anti-herpesvirus therapy 314
Conclusions 316
References 317
Part IV: New Approaches to HHV-6 Research 320
Animal Models 322
Introduction 322
Existing models of viral pathogenesis 323
Epidemiology of HHV-6 infections 324
HHV-6 and MS 325
The common marmoset model of EAE 326
Marmoset model of HHV-6 infection 327
Infection of marmoset cells in vitro 327
Infection of marmosets in vivo 328
Imaging studies and neuropathology 328
Mechanisms of HHV-6-Induced Inflammatory CNS Demyelination 329
Reactivity to viral antigens 329
In vivo persistence and replication of HHV-6 330
Reactivity to CNS myelin antigens 330
HHV-6 has lytic effects on CNS glial cells 333
Conclusions 333
Acknowledgments 334
References 334
Computational Simulation of HHV-6 Infection 340
Introduction 340
Model development 342
Basic model: healthy persons without virus infection 342
Extended model for viral infection 343
Parameter optimization 344
Simulation results 347
Acute HHV-6 infection 347
Chronic HHV-6 infection 348
Discussion 349
References 350
Experimental Therapeutic Approaches 354
Introduction 354
Immunoglobulin 354
Interferon 355
Ampligen 356
Transfer factor 357
Isoprinosine 358
References 358
Colour Section 360
List of Contributors 378
Index 386