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.
Author(s): Ann Arvin, Gabriella Campadelli-Fiume, Edward Mocarski, Patrick S. Moore, Bernard Roizman, Richard W
Edition: 1
Year: 2007
Language: English
Pages: 1408
Cover......Page 1
Half-title......Page 3
Title......Page 5
Copyright......Page 6
Contents......Page 7
Contributors......Page 11
Preface......Page 21
Part I Introduction: definition and classification of the human herpesviruses......Page 23
Morphological criteria......Page 25
Species definition......Page 29
REFERENCES......Page 30
Genome structures......Page 32
Gene content......Page 36
Three major groups......Page 37
The mammalian herpesvirus group......Page 38
The Alphaherpesvirinae subfamily......Page 41
Acknowledgment......Page 42
REFERENCES......Page 43
Summary of virion assembly pathway......Page 49
Different virus-like particles secreted from infected cells......Page 50
Different capsid-like structures inside the infected cells......Page 52
Compositions and three-dimensional structural comparisons of alpha, beta and gammaherpesvirus capsids......Page 53
Structure and packaging of viral genomic DNA......Page 56
Composition of viral tegument......Page 57
Tegument structure of HSV-1......Page 58
Structure and assembly of viral envelope......Page 60
Other constituents in the virions......Page 61
REFERENCES......Page 62
Introduction......Page 66
Virion structural proteins......Page 70
Entry into host cells......Page 72
Regulation of gene expression and replication......Page 73
Viral DNA synthesis and nucleotide metabolism......Page 74
Capsid assembly and DNA encapsidation......Page 75
Maturation......Page 77
REFERENCES......Page 78
Part II Basic virology and viral gene effects on host cell functions: alphaherpesviruses......Page 81
5 Genetic comparison of human alphaherpesvirus genomes......Page 83
VZV genes that are absent from HSV genomes......Page 86
L component genes unique to the simplexviruses......Page 87
S component genes unique to the human simplexviruses......Page 88
REFERENCES......Page 89
Introduction......Page 92
REFERENCES......Page 105
The membrane proteins......Page 115
Attachment to cells......Page 116
gD......Page 117
Receptors......Page 118
gH –gL......Page 122
gB......Page 123
gB......Page 124
Nucleocapsid transport to the nuclear pore......Page 125
Endocytosis of the VZV glycoproteins gE, gB, gH, and the negative regulation of fusion......Page 126
REFERENCES......Page 127
The assembly of the HSV IE enhancer core complex......Page 134
Oct-1......Page 135
VP16......Page 138
HCF-1......Page 140
GABP......Page 142
VZV IE gene expression: parallels and divergence......Page 143
The regulation of the IE genes: reactivation of HSV from the latent state......Page 144
Questions and future directions......Page 145
REFERENCES......Page 146
Viral factors required for the initiation of transcription on HSV-1 and VZV promoters......Page 150
Viral IE proteins that contribute to the induced expression of viral genes......Page 151
RNA processing and transport......Page 153
Concluding remarks......Page 155
REFERENCES......Page 156
The origins of DNA replication......Page 160
Proteins involved in DNA synthesis......Page 161
Recombination......Page 163
REFERENCES......Page 164
Anatomy of the nuclear membrane: it’s all connected......Page 166
The UL31/UL34 protein complex and the nuclear lamina......Page 167
Budding from the nuclear membrane......Page 168
UL37......Page 169
REFERENCES......Page 170
12 The egress of alphaherpesviruses from the cell......Page 173
Evidence and arguments in favor......Page 174
Evidence and arguments against......Page 175
Evidence and arguments in favor......Page 176
Evidence and arguments against......Page 178
US9......Page 179
VZV......Page 180
REFERENCES......Page 181
Gene content, organization, and fundamental design of the viral genome......Page 185
Mobilization of cellular proteins for enhanced replication of HSV......Page 186
The activation of NF-κB......Page 187
Degradation of mRNA in infected cells......Page 188
Specific degradation of cellular proteins in wild-type virus-infected cells......Page 189
HSV blocks pro-apoptotic cellular functions......Page 190
REFERENCES......Page 192
Part II Basic virology and viral gene effects on host cell functions: betaherpesviruses......Page 197
Genome structures......Page 199
Genetic content......Page 200
Gene duplication......Page 208
Gene capture......Page 209
Virion structure......Page 210
The genome......Page 211
The tegument......Page 213
Additional virion components......Page 214
REFERENCES......Page 215
Introduction......Page 226
Virion structural proteins......Page 235
Entry into host cells......Page 236
Regulation of gene expression and replication......Page 238
Viral DNA synthesis and nucleotide metabolism......Page 239
Maturation......Page 240
REFERENCES......Page 241
Introduction......Page 253
Cellular receptors for HCMV......Page 254
Cellular integrins may serve as coreceptors for betaherpesviruses......Page 255
Roles of betaherpesvirus envelope glycoproteins in virus entry......Page 256
REFERENCES......Page 258
Introduction......Page 263
Betaherpesvirus immediate early genes......Page 264
Betaherpesvirus transcriptional enhancers upstream of the MIE genes......Page 265
Function of the betaherpesvirus major immediate–early enhancers......Page 267
Silencing of the immediate-early genes......Page 268
Reactivation of the immediate–early genes......Page 269
Betaherpesvirus major immediate–early genes......Page 270
The IE1 proteins......Page 271
The IE2 proteins......Page 272
Virion components......Page 274
Infection and dysregulation of the cell cycle by betaherpesviruses......Page 275
REFERENCES......Page 276
Identification of HCMV early genes......Page 286
ND10 are sites of genome deposition and IE transcription......Page 287
Inhibition of apoptosis......Page 288
Genes involved directly in viral replication......Page 289
Preparing the cell for viral DNA replication......Page 290
Transactivating functions of the major IE proteins......Page 291
Structure and function of the IE1 72 and IE2 86 kDa proteins......Page 292
Mutational analysis of the major IE products in the viral genome......Page 293
Additional immediate early proteins have regulatory roles......Page 294
UL112–113 transcription is differentially controlled at early and late times......Page 295
Multiple cis-acting sequences regulate UL54 expression......Page 297
UL4 expression is controlled at the transcriptional and translational levels......Page 299
Human herpesviruses 6 and 7......Page 301
HHV-6 IE gene products with regulatory activities......Page 302
IE-B......Page 303
DNA polymerase (U38)......Page 304
Conclusions......Page 305
REFERENCES......Page 306
Overview......Page 317
Helicase–primase complex (UL105, UL70 and UL102)......Page 318
DNA polymerase (UL54) and polymerase accessory protein (UL44)......Page 319
UL84......Page 320
Cytomegalovirus oriLyt......Page 321
Cytomegalovirus oriLyt structure......Page 322
Roseolovirus replication origins......Page 323
Late gene expression......Page 324
REFERENCES......Page 327
Introduction......Page 333
Protein interactions and capsid assembly......Page 334
Capsid maturation and DNA packaging......Page 336
Nuclear tegumentation and nuclear egress......Page 337
Tegument protein trafficking and incorporation into the particle......Page 340
Envelope glycoprotein trafficking and envelopment of the particle......Page 341
REFERENCES......Page 342
21 Viral modulation of the host response to infection......Page 346
Activation of NK-kB and interferon response genes......Page 347
Impact on the host cell cycle......Page 348
Suppression of apoptosis......Page 349
vMIA (pUL37x1)......Page 350
Other cell death suppressors......Page 352
Summary......Page 353
REFERENCES......Page 354
Part II Basic virology and viral gene effects on host cell functions: gammaherpesviruses......Page 361
The gamma-herpesvirus family......Page 363
The discovery of Epstein–Barr virus (EBV)......Page 364
Human disease associated with EBV infection......Page 366
EBV life cycle......Page 367
The discovery of Kaposi’s sarcoma-associated herpesvirus (KSHV)......Page 369
Human disease associated with KSHV infection......Page 370
Phylogenetic relationship between EBV, KSHV, and non-human gamma-herpesvirus genomes......Page 371
Human gamma-herpesviruses genomes......Page 372
Conclusions......Page 373
GENERAL HISTORICAL READING......Page 378
REFERENCES......Page 379
Target cells for KSHV......Page 382
Virion structure......Page 383
Virus structural proteins involved in entry......Page 384
Attachment of EBV......Page 386
Attachment of KSHV......Page 387
Penetration by EBV......Page 388
Penetration by KSHV......Page 391
Signaling by EBV during the early stages of infection......Page 392
Signaling by KSHV during the early stages of infection......Page 393
Cytoplasmic trafficking, delivery of viral genome into the nucleus......Page 395
REFERENCES......Page 396
Introduction......Page 401
Properties of the episomal latent viral genome......Page 402
DNA methylation of latent EBV......Page 403
Molecular biology of OriP......Page 404
C-terminal DNA binding domain......Page 406
Transcription regulation......Page 407
Cellular proteins that interact with OriP......Page 408
Mechanism of viral chromosome replication......Page 409
The KSHV episome in latently infected cells......Page 410
Modular domain structure of LANA......Page 411
Mechanism of episomal segregation and chromosome tethering......Page 412
Identification of a DS-like element within TR......Page 413
Trans-requirements for LANA and interaction with cellular ORC proteins......Page 414
EBV and KSHV origins and origin binding proteins: conserved and diverged?......Page 415
REFERENCES......Page 417
Viral pathogenesis......Page 425
Stimuli that induce lytic EBV infection......Page 426
Organization of the IE gene region of EBV......Page 427
Cellular factors which activate Zp......Page 428
Regulation of Rp......Page 430
Host cell and viral factors which influence stringency of viral latency......Page 431
BZLF1 transcriptional effects......Page 432
The BZLF1-knockout virus is less efficient in promoting lymphoproliferative disease in SCID mice......Page 433
BZLF1 effects on p53......Page 434
BZLF1 effects on the host immune response......Page 435
The role of BRLF1 in lytic induction......Page 436
BRLF1-knockout virus phenotype......Page 437
BRLF1 cell cycle effects......Page 438
Transcription factors......Page 439
Viral replication......Page 440
Late viral gene regulation......Page 441
Treatment of lytic EBV infection......Page 442
Unresolved issues for the future......Page 443
REFERENCES......Page 444
Lytic reactivation of KSHV is a critical pathogenic step in development of KS and other human diseases......Page 456
The immune system tempers lytic reactivation of KSHV and KS development......Page 457
MHV-68 is a model for immune control of gamma-herpesvirus reactivation from latency......Page 458
Sites of latency and reservoirs for viral amplification in vivo......Page 459
Kinetic classification of KHSV lytic gene expression......Page 460
ORF50/Rta is the viral lytic switch protein......Page 461
Signals that control lytic reactivation of KSHV......Page 464
Shut-off of host gene expression......Page 467
K8/KbZIP and ORF50/Rta are origin-binding proteins that are responsible for recruiting pre-replication complexes to ori-Lyt DNA......Page 468
Viral enzymes and accessory factors essential for KSHV ori-Lyt-specific DNA replication and DNA replication machinery......Page 470
DNA polymerase and processivity factor......Page 471
Late genes and KSHV virion structure......Page 472
REFERENCES......Page 473
Virus and genome structure......Page 483
The lymphoblastoid cell line LCL......Page 484
Other forms of EBV latency......Page 487
EBV replication/the lytic cascade......Page 489
DNA replicative enzymes......Page 491
BARF1......Page 492
Glycoproteins......Page 493
EBV persistence in vivo......Page 494
EBV strain variation......Page 496
Function of the EBV latent genes: from persistence to pathology......Page 497
EBNA3 family......Page 498
LMP1......Page 499
BARTs......Page 500
Conclusions......Page 501
REFERENCES......Page 502
PEL derived cell lines......Page 512
Viral gene expression in vivo......Page 516
KS lesions......Page 517
Multicentric Castleman’s disease......Page 518
Genomic region containing KSHV latent genes and the viral chemokine receptor homologue......Page 519
Genomic region containing immediate-early genes......Page 520
vIRF Locus......Page 522
Terminalmembrane proteins......Page 524
“Kaposin” locus......Page 525
Other spliced genes in the KSHV genome......Page 527
Events leading to the activation of immediate–early and early KSHV genes......Page 528
Other factors that increase lytic viral replication......Page 530
REFERENCES......Page 531
Early history: up and down......Page 536
Classes of experimental tumor viruses......Page 537
Human tumor viruses......Page 539
EBV exploits B-cell specific regulatory mechanisms and signals......Page 540
Growth transformation associated EBV encoded proteins......Page 541
EBNA2......Page 542
EBNA 3 (alt: EBNA 3a)......Page 543
The latent membrane proteins (LMP) of EBV......Page 544
Latent membrane proteins 1 (LMP1)......Page 545
LMP2 modulation of signaling in B-cells and epithelial cells......Page 546
EBV and Burkitt lymphoma (BL)......Page 547
Hodgkin’s lymphoma (HL)......Page 548
Immune surveillance and the oncogenic herpesviruses – the role of immunological “anticipation”......Page 549
Double HHV8/EBV carrying PEL cells......Page 551
Conclusions......Page 552
REFERENCES......Page 556
30 KSHV manipulation of the cell cycle and apoptosis......Page 562
LANA-1......Page 563
LANA......Page 564
Viral Cyclin (vCYC)......Page 566
K1 Protein......Page 568
Virus-encoded chemokines and cytokines......Page 569
Disarming the guardian: p53 inhibition......Page 570
RTA, K-bZIP and vIRF1......Page 572
The mitochondrial anti-apoptotic proteins: vBCL-2, vIAP......Page 573
REFERENCES......Page 574
Evasion of innate host immunity......Page 581
Complement deregulation......Page 582
Interleukin and chemokine responses......Page 585
Interferon responses......Page 589
Apoptosis responses......Page 593
Natural killer (NK) cell responses......Page 595
Evasion of other innate cellular responses......Page 597
Evasion of CTL responses......Page 598
Evasion of CD4+ T helper cell and B cell responses......Page 599
REFERENCES......Page 601
Part III Pathogenesis, clinical disease, host response, and epidemiology: alphaherpes viruses......Page 609
Unique biologic properties of HSV that influence pathogenesis......Page 611
Pathology of central nervous system disease......Page 613
Impact of host response to infection on disease......Page 614
Primary infection......Page 618
Central nervous system infections......Page 619
Infection in compromised hosts......Page 620
REFERENCES......Page 621
Model systems to study latency......Page 624
The latent genome......Page 625
The LAT promoter......Page 626
A block to HSV IE transcription......Page 628
Role of LAT in the establishment of latency......Page 629
Maintenance of latency......Page 630
The role of ICP0 in reactivation......Page 631
Cellular reactivation signals......Page 632
The role of LAT in reactivation......Page 633
REFERENCES......Page 634
HSV interactions with dendritic cells......Page 638
CD8 T-cell responses to HSV......Page 640
CD4 T-cell responses to HSV......Page 643
T-cell costimulation and HSV......Page 645
Innate immunity......Page 646
NK cells......Page 650
TCRgammaδ cells......Page 651
REFERENCES......Page 652
Introduction......Page 664
Keratitis in humans......Page 665
Innate reactions to infection in the mouse model......Page 667
Adaptive immunity in SK......Page 669
Acute retinal necrosis (ARN) in humans......Page 671
Ganglionitis......Page 672
REFERENCES......Page 673
Epidemiology of HSV-1 and HSV-2......Page 678
Genital herpes......Page 679
Other mucocutaneous infections......Page 680
Eye disease......Page 681
Neonatal herpes......Page 682
Immunocompromised persons......Page 683
Viral shedding......Page 684
Treatment......Page 685
Severe HSV infection......Page 686
REFERENCES......Page 688
Part III Pathogenesis, clinical disease, host response, and epidemiology: alphaherpes viruses VZV......Page 695
Systems for evaluating determinants of VZV pathogenesis in human skin and T-cells......Page 697
Effects of VZV replication on cellular cyclin-dependent kinases and cyclins......Page 698
Investigation of events in the pathogenesis of primary VZV infection in the SCIDhu model......Page 699
Glycoprotein E......Page 701
The role of regulatory proteins and viral kinases in T-cell and skin tropism......Page 702
ORF64 protein......Page 703
ORF47 protein......Page 704
Disease consequences of primary VZV infection in healthy and immunocompromised hosts......Page 705
Varicella in the immunocompromised host......Page 707
REFERENCES......Page 708
Quantification of VZV DNA load during latency......Page 711
Animal models for VZV latency......Page 712
VZV transcripts expressed during latency......Page 713
VZV proteins expressed during latency......Page 714
In vitro models for VZV latency......Page 715
Comparison of VZV latency with that of other alphaherpesviruses......Page 716
VZV proteins localize to the cytoplasm, instead of the nucleus of neurons and thus are unable to carry out their activities......Page 717
REFERENCES......Page 718
VZV encoded downmodulation of cell-surface MHC class I expression......Page 722
VZV encoded inhibition of IFN gamma-mediated up-regulation of cell-surface MHC class II......Page 724
VZV infection of human dendritic cells and transmission to T-cells......Page 726
VZV encodes an immune evasion strategy during the productive infection of mature dendritic cells......Page 728
Immunity during primary VZV infection......Page 729
Persistence of VZV-specific memory......Page 730
REFERENCES......Page 731
Transmission......Page 735
Periodicity and seasonality......Page 736
Age and climate......Page 737
Other factors: sex, race, number of siblings in the household and child care......Page 739
Hospitalization and deaths......Page 740
Varicella epidemiology: post-vaccine era......Page 741
Methodological issues......Page 743
Age......Page 744
Race......Page 746
Immunocompromising states......Page 747
Complications......Page 748
Deaths......Page 749
Impact of vaccination......Page 750
REFERENCES......Page 751
Part III Pathogenesis, clinical disease, host response, and epidemiology: betaherpesviruses......Page 757
Introduction......Page 759
Sources of HCMV in the community......Page 760
Acquisition of HCMV by sexual contact......Page 762
Sources of HCMV in hospitalized patients and health-care workers......Page 763
Reinfection: acquisition of HCMV by a previously infected host......Page 765
Infection following community exposure......Page 766
Transfusion and allograft-acquired infection......Page 767
Cell-associated spread within the host......Page 768
Viral genes associated with virulence: viral dissemination and in vivo tropism......Page 769
Disease and HCMV infection: pathogenesis of end-organ disease in acute infection......Page 771
Disease and HCMV infection: pathogenesis of end-organ disease related to chronic infections......Page 772
REFERENCES......Page 775
ECs are a site of persistent HCMV replication......Page 787
Determinants of EC tropism......Page 789
Myeloid lineage cells are a site of HCMV latency......Page 790
Growth of HCMV in Con A-MDM......Page 791
Growth of HCMV in Allo-MDM......Page 792
Determinants of myeloid lineage cell tropism......Page 795
Summary......Page 796
REFERENCES......Page 797
Cells of the immune system as sites of latency and reactivation for HCMV......Page 802
Antibody and complement......Page 803
The HCMV specific CD8+ T-cell response......Page 804
The HCMV-specific CD4+ T-cell response......Page 807
HCMV, innate immunity and natural killer (NK) cells......Page 808
Immunopathology in human CMV disease CMV pneumonitis......Page 810
CMV and organ transplant rejection......Page 811
REFERENCES......Page 812
Epidemiology of HCMV infection......Page 817
Transmission of HCMV by mothers to infants: perinatal infections......Page 818
Children-to-children transmission of HCMV......Page 819
Transmission of HCMV by children to parents......Page 821
HCMV transmission through sexual activity......Page 822
Transmission of HCMV to child-care providers......Page 824
Transmission of CMV in health-care settings......Page 825
Transfusion acquired HCMV infection......Page 827
Transplantation and HCMV infection......Page 828
REFERENCES......Page 829
Diverse cell types in the uterus......Page 836
Invasive cytotrophoblasts modulate the expression of stage-specific antigens......Page 838
CMV protein expression in placental cells in chorionic villi infected in vitro and in utero......Page 839
Pathogenic microorganisms at the placental–decidual interface......Page 840
Neutralizing antibodies to CMV gB in placental syncytiotrophoblasts......Page 841
Different patterns of CMV infection in the decidua mirrored in the adjacent placenta......Page 842
Complexes of IgG and CMV virions transcytosed from maternal circulation across syncytiotrophoblasts to underlying cytotrophoblasts......Page 845
CMV infection in vitro downregulates alpha 1beta1 integrin expression and impairs cytotrophoblast invasion......Page 846
CMV infection downregulates MMP activity altering cell-cell and cell–matrix interactions......Page 847
CMV IL-10 dysregulates MMP activity......Page 848
REFERENCES......Page 849
Part III HHV-6A, 6B, and 7......Page 853
Cell tropism in vitro......Page 855
Entry......Page 856
Effects of virus infection on host cells......Page 858
Reactivation of HHV-6 and its clinical symptoms......Page 860
REFERENCES......Page 861
Latency-associated transcripts of HHV-6......Page 865
First molecular event of HHV-6 reactivation......Page 866
REFERENCES......Page 869
Cell tropism......Page 872
In vivo......Page 873
Lytic antigens......Page 875
Targets of complement independent neutralization......Page 876
Targets for diagnosis......Page 877
HHV-6 and HHV-7......Page 878
IgMantibodies......Page 879
Neutralizing antibodies......Page 880
Allogeneic bonemarrow and blood stemcell transplantation......Page 881
Multiple sclerosis (MS)......Page 882
Stemcells......Page 883
T-lymphocytes......Page 884
T-cell apoptosis......Page 885
Cytokine production......Page 886
Clinical significance of immunomodulation......Page 887
REFERENCES......Page 888
Epidemiology of HHV-6 and HHV-7......Page 897
HHV-6 and HHV-7 genotypes......Page 898
HHV-6 integration......Page 899
Concluding comments......Page 900
REFERENCES......Page 901
Part III Pathogenesis, clinical disease, host response, and epidemiology: gammaherpesviruses......Page 905
Infection in the normal host......Page 907
Chronic active EBV......Page 908
EBV-associated tumors......Page 909
Burkitt’s lymphoma......Page 911
Post transplant lymphoproliferative disorders (PTLD)......Page 912
Nasopharyngeal carcinoma......Page 913
Other EBV-associated tumors......Page 914
Kaposi’s sarcoma......Page 915
Treatment......Page 916
Castleman’s disease and plasmablastic lymphomas......Page 917
Primary effusion lymphoma and related lymphomas......Page 918
REFERENCES......Page 919
Introduction......Page 926
Response during acute infection......Page 927
Role of CD4+ and CD8+ CTL in control of EBV infection......Page 929
T-cell receptor usage......Page 930
Modulation of the cytokine network......Page 931
Regulation of antigen processing and presentation......Page 932
T-cell control of EBV-associated malignancies......Page 933
REFERENCES......Page 934
Primary infection......Page 937
Dendritic cells......Page 939
Natural killer cells......Page 940
CTL epitopes......Page 941
Antibody epitopes and serological assays for anti-KSHV antibody detection......Page 943
How antibodies contribute to KSHV immunity......Page 945
FURTHER READING......Page 946
REFERENCES......Page 947
Geographic variation......Page 951
Socioeconomic factors......Page 952
EBV viral load epidemiology......Page 953
Infectious mononucleosis......Page 954
EBV dynamics during infectious mononucleosis......Page 955
Chronic active EBV infection......Page 956
X-linked lymphoproliferative syndrome......Page 957
Epidemiology......Page 958
Evidence of association with EBV......Page 960
Tumors of the lymphoid tissues......Page 961
Burkitt’s lymphoma/leukemia......Page 962
NK/T-cell lymphomas......Page 963
Hodgkin’s lymphoma......Page 964
Lymphoproliferative disease associated with immunodeficiency......Page 966
Epidemiology......Page 969
Lymphoepithelioma-like carcinomas......Page 970
REFERENCES......Page 972
Initial serologic assays for KSHV antibodies......Page 982
Methodologic challenges in serologic assay development......Page 983
Recently developed eukaryotically derived recombinant antigen-based serologic assays......Page 984
Prevalence of infection Geographic distribution......Page 985
Genotypic diversity of infection......Page 986
Sexual transmission......Page 988
Organ transplantation......Page 992
Non-sexual horizontal transmission......Page 993
Sexual transmission......Page 994
Primary infection syndrome......Page 995
Kaposi’s sarcoma......Page 996
REFERENCES......Page 1000
EBV infection in vivo......Page 1008
EBV expression in latent infection......Page 1010
Latent membrane protein 1......Page 1012
EBV-encoded RNAs (EBER)......Page 1013
Malignancies associated with EBV......Page 1014
Characteristics of EBV Infection in BL......Page 1015
Nasopharyngeal carcinoma......Page 1016
Characteristics of EBV infection in NPC......Page 1017
Hodgkin’s lymphoma......Page 1018
Tumor suppressor inactivation......Page 1019
EBV strain variation......Page 1020
EBV-targeted therapy......Page 1022
REFERENCES......Page 1023
Primary effusion lymphoma (PEL)......Page 1029
Latency-associated nuclear antigen (LANA)......Page 1030
v-cyclin......Page 1032
v-FLIP......Page 1033
Kaposin......Page 1034
Multicentric Castleman’s disease (MCD)......Page 1036
Kaposi’s sarcoma......Page 1037
KSHV gene expression in KS......Page 1039
Conclusions......Page 1042
REFERENCES......Page 1043
Part IV Non-human primate herpesviruses......Page 1051
History......Page 1053
Distribution in nature......Page 1054
The B virus genome......Page 1055
Pathology and pathogenesis......Page 1056
Experimental infections......Page 1057
Human infection......Page 1058
Animals......Page 1059
Host immune responses......Page 1060
Non-human primates......Page 1061
Control of B virus infection......Page 1062
REFERENCES......Page 1063
Introduction......Page 1065
Simian varicella virus genome......Page 1066
SVV pathogenesis......Page 1067
REFERENCES......Page 1071
Historical evidence of CMV in NHP......Page 1073
Pathogenesis......Page 1074
Immunological parameters of primary infection......Page 1075
Virological and immunological parameters of chronic infection......Page 1076
Retroviral-induced immunodeficiency......Page 1077
Transplantation......Page 1078
Fetal Infection......Page 1079
Genome coding content......Page 1080
Gene arrangements......Page 1083
Genomic DNA sequences......Page 1087
Betaherpesvirus-specific proteins......Page 1088
Primate CMV-specific proteins......Page 1090
REFERENCES......Page 1092
Natural occurrence and pathology......Page 1098
Genome structure and replication......Page 1099
Immunomodulatory proteins......Page 1100
Oncogenesis......Page 1102
Growth transformation of human T-cells......Page 1105
Natural occurrence and pathology......Page 1106
Oncogenesis......Page 1107
REFERENCES......Page 1108
Nomenclature......Page 1115
The rhesus LCV genome......Page 1117
Epstein–Barr virus nuclear antigen- 3A,3B,3C (EBNA-3A, 3B, 3C)......Page 1120
Rhesus LCV as an animal model system for EBV......Page 1121
Lymphocryptoviruses of New World monkeys......Page 1122
CalHV3 ORF39 (EBNA-1)......Page 1123
Evolution of New and Old World rhadinoviruses......Page 1124
Retroperitoneal fibromatosis herpesviruses: RFHVMm and RFHVMn......Page 1125
Genomic organization of RRV......Page 1126
RRV vIL6......Page 1127
RRV capsid structure......Page 1128
RRV pathogenesis......Page 1129
Conclusions......Page 1130
REFERENCES......Page 1131
Part V Subversion of adaptive immunity......Page 1137
62 Herpesvirus evasion of T-cell immunity......Page 1139
Interference with proteasomal proteolysis......Page 1141
Interference with peptide transport......Page 1143
Destruction of class I molecules via proteasomal proteolysis......Page 1144
Disruption of the class I secretory pathway......Page 1147
Retrieval of cell surface class I molecules......Page 1148
Interference with class I molecules at the cell surface......Page 1149
Interference with APC function......Page 1150
Erroneous T-cell activation......Page 1151
Manipulation of class II molecules......Page 1152
REFERENCES......Page 1153
Introduction......Page 1159
IgG Fc receptors on mammalian cells......Page 1160
gE and gI structure......Page 1161
The HSV-1 FcgammaR and immune evasion......Page 1162
Murine CMV......Page 1163
Introduction......Page 1164
HSV-1 and HSV-2 glycoprotein gC......Page 1165
Viruses that incorporate human complement regulatory proteins into their envelope during viral maturation and egress: human CMV......Page 1167
HVS: CD59......Page 1168
REFERENCES......Page 1169
Part VI Antiviral therapy......Page 1173
Acyclovir......Page 1175
Clinical efficacy inHSV-1 and HSV-2 infections......Page 1176
Antiviral resistance......Page 1183
Challenges for achieving clinical benefit, including adverse drug effects......Page 1184
Clinical efficacy inHSV-1 and HSV-2 infections......Page 1185
Antiviral resistance......Page 1186
Challenges for achieving clinical benefit, including adverse drug effects......Page 1187
Clinical efficacy in HSV-1 and HSV-2 infections......Page 1188
Mechanism of action and pharmacokinetics......Page 1189
Dosage regimens......Page 1190
REFERENCES......Page 1191
Diagnosis......Page 1197
Acyclovir and valacyclovir......Page 1199
Penciclovir and famciclovir......Page 1200
Children......Page 1201
Adults......Page 1202
Immunocompetent adults......Page 1203
Herpes zoster ophthalmicus......Page 1206
HIV-seropositive patients......Page 1207
Immunocompromised (including HIV-seropositive) patients......Page 1208
Drug-resistant varicella-zoster virus......Page 1209
REFERENCES......Page 1210
Nucleotides......Page 1214
Clinical efficacy; challenges for achieving clinical benefit......Page 1215
Viremia and viral load......Page 1216
Clinical manifestations of CMV end-organ disease......Page 1218
Detection of viremia......Page 1219
Strategies for deploying antiviral agents......Page 1220
Results of double-blind, randomized, placebo-controlled trials......Page 1221
Aspects of CMV management in HIV-infected individuals......Page 1223
Conclusions......Page 1224
Gene UL 97......Page 1225
Patterns of cross-resistance......Page 1226
Recognition of resistance in clinical practice......Page 1227
REFERENCES......Page 1228
Development of bioinformatics and computational tools......Page 1233
Impact of genomics and related fields on herpesvirus research......Page 1234
New resources for use in drug discovery......Page 1235
Application of new technologies to biochemical assays......Page 1236
Application of new technologies to characterize mechanism of action and spectrum of activity......Page 1237
REFERENCES......Page 1238
The drug development process: an overview......Page 1241
Host cell targets as an approach to virus inhibition......Page 1247
PD146626......Page 1248
Antiviral targets in the herpesvirus DNA replication complex......Page 1249
Nucleoside/nucleotide analogue inhibitors......Page 1250
Non-nucleotide inhibitors......Page 1253
Herpes helicase-primase inhibitors......Page 1254
WAY 150138......Page 1257
Dihydroxyacridone series......Page 1258
GW275175X......Page 1259
Protease inhibitors......Page 1260
Indolocarbazoles......Page 1261
Maribavir......Page 1262
Antivirals with activity against EBV, HHV-6, HHV-7, and HHV-8......Page 1264
REFERENCES......Page 1265
Part VII Vaccines and immunotherapy......Page 1273
Introduction......Page 1275
Development of live, attenuated vaccines......Page 1276
Subunit vaccines......Page 1278
Conclusions......Page 1280
REFERENCES......Page 1281
History of development of the live attenuated vaccine......Page 1284
Safety of the varicella vaccine for healthy individuals......Page 1285
Efficacy and post-licensure effectiveness of varicella vaccine......Page 1286
Considerations of vaccine use......Page 1287
Does immunity to varicella wane with time after immunization?......Page 1288
Zoster: effects and potential effects on its incidence in the vaccine era......Page 1290
Recent developments......Page 1291
Conclusions......Page 1292
REFERENCES......Page 1293
The case for a cytomegalovirus vaccine......Page 1296
Natural immunity confers protection......Page 1297
Immunology of HCMV protection......Page 1298
Replicating vaccines......Page 1300
Subunit vaccines......Page 1303
Vectored vaccines......Page 1304
DNA vaccines......Page 1305
Subviral particles......Page 1306
REFERENCES......Page 1307
Introduction......Page 1314
Vaccines to prevent infectious mononucleosis......Page 1316
Gp350......Page 1317
EBNA3......Page 1318
Therapeutic vaccines to prevent Hodgkin’s disease and nasopharygeal carcinoma......Page 1319
LMP polyepitope vaccines......Page 1320
Altered antigen processing of LMPs using bacterial toxins......Page 1321
Therapeutic vaccines for Burkitt’s lymphoma......Page 1322
Conclusions......Page 1323
REFERENCES......Page 1324
Mechanism of action......Page 1328
DNA vaccines: advantages and disadvantages......Page 1329
Features of pDNA constructs especially conducive to herpesvirus vaccine development......Page 1331
Animal and human experience with DNA vaccines......Page 1332
Genes of interest......Page 1333
Animal studies......Page 1334
Genes of interest......Page 1335
REFERENCES......Page 1336
Therapy for herpesvirus-related infections and diseases......Page 1340
Epstein–Barr virus......Page 1341
T-cell activation......Page 1342
Adoptive immunotherapy for cytomegalovirus......Page 1343
Adoptive immunotherapy for EBV post-transplant lymphoproliferation disease......Page 1344
Adoptive immunotherapy for EBV post-solid organ transplant......Page 1345
Adoptive transfer of EBV-specific CTL for nasopharyngeal carcinoma......Page 1346
Clones vs. polyclonal lines......Page 1347
APC......Page 1348
Regulation......Page 1349
REFERENCES......Page 1350
Neonates......Page 1354
Neonates......Page 1355
Animal models of antibody immunotherapy in HSV infection and disease......Page 1356
Summary......Page 1357
REFERENCES......Page 1358
Part VIII Herpesviruses as Therapeutic Agents......Page 1361
Properties of therapeutic HSV vectors......Page 1363
Use of HSV vectors to modify the nervous system......Page 1364
Central nervous system (CNS)......Page 1365
Towards optimizing HSV vectors for therapeutic use......Page 1366
Introduction......Page 1367
Oncolytic HSV in malignant glioma......Page 1368
NV1020: colorectal metastases......Page 1370
Oncolytic HSV: current directions......Page 1371
REFERENCES......Page 1372
Index......Page 1375
