Front Matter

Cambridge University Press 978-0-521-82714-0 - Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis Edited by Ann Arvin, Gabriella Campadelli-Fiume, Edward Mocarski, Patrick S. Moore, Bernard Roizman, Richard Whitley and Koichi Yamanishi Frontmatter More information

Human Herpesviruses

This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi’s Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B, and 7, and varicella-zoster virus. The viral diseases and cancers they cause are signiﬁcant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysi- ology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientiﬁcally and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.

ann arvin is Professor of Pediatrics, Microbiology, and Immunology at Stanford University.

gabriella campadelli-ﬁume is Professor of Micro- biology and Virology at the University of Bologna, Italy.

edward mocarski is Professor of Microbiology and Immunology at Emory University.

patrick moore is Professor of Molecular Genetics and Biochemistry at the University of Pittsburgh.

bernard roizman is Professor of Molecular Genetics, Cell Biology, Biochemistry, and Molecular Biology at the University of Chicago.

richard whitley is Professor of Pediatrics, Microbi- ology, Medicine, and Neurosurgery at the University of Alabama Birmingham.

koichi yamanishi is Professor of Microbiology at Osaka University, Japan.

© Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-82714-0 - Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis Edited by Ann Arvin, Gabriella Campadelli-Fiume, Edward Mocarski, Patrick S. Moore, Bernard Roizman, Richard Whitley and Koichi Yamanishi Frontmatter More information

Human Herpesviruses Biology, Therapy, and Immunoprophylaxis

Edited by Ann Arvin Stanford University, CA School of Medicine Gabriella Campadelli-Fiume University of Bologna, Italy Edward Mocarski Emory University School of Medicine, USA Patrick S. Moore University of Pittsburgh Cancer Institute, PA, USA Bernard Roizman The University of Chicago, IL, USA Richard Whitley University of Alabama at Birmingham, AL, USA Koichi Yamanishi Osaka University School of Medicine, Japan

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Every effort has been made in preparing this Publication to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

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Contents

List of contributors page ix Preface xix

Part I Introduction: definition and classification of the human herpesviruses

Bernard Roizman

1 Overview of classiﬁcation 3 Andrew Davison

2 Comparative analysis of the genomes 10 Andrew Davison

3 Comparative virion structures of human herpesviruses 27 Fenyong Liu and Z. Hong Zhou

4 Comparative analysis of herpesvirus–common proteins 44 Edward Mocarski, Jr.

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

Gabriella Campadelli-Fiume and Bernard Roizman

5 Genetic comparison of human alphaherpesvirus genomes 61 Joel Baines and Philip Pellett

6 Alphaherpes viral genes and their functions 70 Bernard Roizman and Gabriella Campadelli-Fiume

7 Entry of alphaherpesviruses into the cell 93 Gabriella Campadelli-Fiume and Laura Menotti

vi Contents

8 Early events pre-initiation of alphaherpes viral Part II Basic virology and viral gene effects on gene expression 112 host cell functions: gammaherpesviruses Thomas Kristie Patrick S. Moore 9 Initiation of transcription and RNA synthesis, 22 Introduction to the human ␥-herpesviruses 341 processing, and transport in HSV and VZV Richard Longnecker and Frank Neipel infected cells 128 Rozanne Sandri-Goldin 23 Gammaherpesviruses entry and early events during infection 360 10 Alphaherpesvirus DNA replication 138 Bala Chandran and Lindsey Hutt-Fletcher John Hay and William Ruyechan

11 Envelopment of HSV nucleocapsids at the 24 Gammaherpesvirus maintenance and inner nuclear membrane 144 replication during latency 379 Joel Baines Paul Lieberman, Jianhong Hu, and Rolf Renne

12 The egress of alphaherpesviruses from the cell 151 25 Reactivation and lytic replication of EBV 403 Gabriella Campadelli-Fiume Shannon Kenney

13 The strategy of herpes simplex virus replication 26 Reactivation and lytic replication of KSHV 434 and takeover of the host cell 163 David Lukac and Yan Yuan Bernard Roizman and Brunella Taddeo 27 EBV gene expression and regulation 461 Part II Basic virology and viral gene effects on Lawrence S. Young, John R. Arrand, and Paul G. Murray host cell functions: betaherpesviruses 28 KSHV gene expression and regulation 490 Edward Mocarski Thomas Schultz and Yuan Chang

14 Comparative betaherpes viral genome and 29 Effects on apoptosis, cell cycle and virion structure 177 transformation, and comparative aspects of Andrew Davison and David Bhella EBV with other DNA tumor viruses 514 15 Betaherpes viral genes and their functions 204 George Klein and lngemar Emberg Edward Mocarski 30 KSHV manipulation of the cell cycle and 16 Early events in human cytomegalovirus programmed cell death pathways 540 infection 231 Patrick Moore Teresa Compton and Adam Feire 31 Human gammaherpesvirus immune evasion 17 Immediate–early CMV gene regulation and strategies 559 function 241 Robert Means, Sabine Lang, and Jae Jung Mark Stinski and Jeffrey Meier

18 Early CMV gene expression and function 264 Elizabeth White and Deborah Spector Part III Pathogenesis, clinical disease, host response, and epidemiology: 19 CMV DNA synthesis and late viral gene HSV-1 and HSV-2 expression 295 David Anders, Julie Kerry and Gregory Pari Ann Arvin and Richard Whitley

20 CMV maturation and egress 311 32 HSV-1 AND 2: pathogenesis and disease 589 William Britt Richard Whitley, David Kimberlin, and Charles Prober

21 CMV modulation of the host response to 33 HSV-1 and 2: molecular basis of HSV latency infection 324 and reactivation 602 A. Louise McCormick and Edward Mocarski, Jr. Christopher Preston and Stacey Efstathiou

Contents vii

34 HSV-1 and 2: immunobiology and host 45 HCMV: persistence in the population: potential response 616 transplacental transmission 814 David Koelle Lenore Peirera, Ekaterina Maidji, and Susan Fisher

35 HSV: immunopathological aspects of HSV infection 642 Part III Pathogenesis, clinical disease, host Kaustuv Banerjee and Barry Rouse response, and epidemiology: 36 HSV: persistence in the population: HHV- 6A, 6B, and 7 epidemiology, transmission 656 Ann Arvin and Richard Whitley Anna Wald and Lawrence Corey 46 HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease 833 Part III Pathogenesis, clinical disease, host Yasuko Mori and Koichi Yamanishi response, and epidemiology: 47 HHV-6A, 6B, and 7: molecular basis of latency VZU and reactivation 843 Ann Arvin and Richard Whitley Kaszuhiro Kondo and Koichi Yamanishi

37 VZV: pathogenesis and the disease 48 HHV-6A, 6B, and 7: immunobiology and host consequences of primary infection 675 response 850 Jennifer Moffat, Chia-chi Ku, Leigh Zerboni, Marvin Fu-Zhang Wang and Philip Pellet Sommer, and Ann Arvin 49 HHV-6A, 6B, and 7: persistence in the 38 VZV: molecular basis of persistence (latency population: epidemiology, transmission 875 and reactivation) 689 Vincent Emery and Duncan Clark Jeffrey Cohen

39 VZV: immunobiology and host response 700 Part III Pathogenesis, clinical disease, host Ann Arvin and Allison Abendroth response, and epidemiology: gammaherpesviruses 40 VZV: persistence in the population: transmission and epidemiology 713 Patrick S. Moore Jane Seward and Aisha Jumaan 50 Clinical and pathological aspects of EBV And KSHV infection 885 Richard Ambinder and Ethel Cesarman Part III Pathogenesis, clinical disease, host response, and epidemiology: 51 EBV: Immunobiology and host response 904 HCMV Denis Moss, Scott Burrows, and Rajiv Khanna

Ann Arvin and Richard Whitley 52 Immunobiology and host response to KSHV infection 915 41 HCMV: pathogenesis and disease Dimitrios Lagos and Chris Boshoff consequences 737 William Britt 53 The epidemiology of EBV and its association with malignant disease 929 42 HCMV: molecular basis of persistence and Henrik Hjalgrim, Jeppe Friborg, and Mads Melbye latency 765 Michael Jarvis and Jay Nelson 54 The epidemiology of KSHV and its association with malignant disease 960 43 HCMV: immunobiology and host response 780 Jeffrey Martin Mark Wills, Andrew Carmichael, J. H. Sinclair, and J. G. Patrick Sissons 55 EBV-induced oncogenesis 986 Nancy Raab-Traub 44 HCMV: persistence in the population: epidemiology and transmission 795 56 KSHV-induced oncogenesis 1007 Suresh Boppana and Karen Fowler Donald Ganem

viii Contents

Part IV Non-human primate herpesviruses 67 New approaches to antiviral drug discovery (genomics/proteomics) 1211 Ann Arvin, Patrick Moore, and Richard Whitley Mark Prichard 57 Monkey B virus 1031 68 Candidate anti-herpesviral drugs; mechanisms Julia Hilliard of action and resistance 1219 58 Simian varicella virus 1043 Karen Biron Ravi Mahalingam and Donald Gilden

59 Primate betaherpesviruses 1051 Peter Barry and William Chang Part VII Vaccines and immunothgerapy

60 Gammaherpesviruses of New World primates 1076 Ann Arvin and Koichi Yamanishi Armin Ensser and Bernhard Fleckenstein 69 Herpes simplex vaccines 1253 61 EBV and KSHV-related herpesviruses in George Kemble and Richard Spaete non-human primates 1093 Blossom Damania 70 Varicella-zoster vaccine 1262 Anne Gershon

Part V Subversion of adaptive immunity 71 Human cytomegalovirus vaccines 1274 Thomas Heineman Richard Whitley and Ann Arvin 72 Epstein–Barr virus vaccines 1292 62 Herpesvirus evasion of T-cell immunity 1117 Andrew Morgan and Rajiv Khanna Jatin Vyas, Benjamin Gewurz, and Hidde Ploegh 73 DNA vaccines for humanherpesviruses 1306 63 Subversion of innate and adaptive immunity: Thomas Evans and Mary Wloch immune evasion from antibody and complement 1137 74 Adoptive immunotherapy for herpesviruses 1318 Lauren Hook and Harvey Friedman Ann M. Leen, Uluhan Sili, Catherine Bollard, and Cliona Rooney

Part VI Antiviral therapy 75 Immunotherapy of HSV infections – antibody delivery 1332 Richard Whitley David Kimberlin 64 Antiviral therapy of HSV-1 and -2 1153 David Kimberlin and Richard Whitley Part VIII Herpes as therapeutic agents 65 Antiviral therapy of varicella-zoster virus infections 1175 Richard Whitley and Bernard Roizman John Gnann, Jr. 76 Herpesviruses as therapeutic agents 1341 66 Antiviral therapy for human Frank Tufaro and James Markert cytomegalovirus 1192 Paul Griffiths and Michael Boeckh Index 1353

Contributors

Allison Abendroth Centre for Virus Research Westmead Millennium Institute and Research Centres Westmead NSW 2145 Australia

Richard Ambinder Johns Hopkins University School of Medicine 1650 Orleans Street, Room 389 Baltimore, MD 21231, USA

David Anders Wadsworth Center The David Axelrod Institute PO Box 22002 Albany, NY 12201, USA

John Arrand Cancer Research UK Institute for Cancer Studies University of Birmingham Edgbaston, Birmingham B15 2TT, UK

Ann Arvin Department of Pediatrics and Microbiology and Immunology Stanford University School of Medicine 300 Pasteur Drive, Room G311 Stanford, CA 94305, USA

Joel Baines Cornell University Department of Microbiology and Immunology C5169 Veterinary Education Ctr. Ithaca, NY 14853, USA

x Contributors

Kasstruf Banerjee William Britt Department of Microbiology Department of Pediatrics College of Veterinary Medicine University of Alabama at Birmingham University of Tennessee CHB 107, 1600 7th Avenue South 1414 W. Cumberland Avenue Birmingham, AL, 35233, USA F403 Walters Life Sciences Knoxville, TN 37996, USA Scott Burrows Division of Infectious Diseases and Immunology Peter Barry Queensland Institute of Medical Research Department of Pathology 300 Herston Road Center for Comparative Medicine Herston (Qld) 4006 University of California at Davis Australia One Shields Avenue Davis, CA 95616, USA Gabriella Campadelli-Fiume Department of Experimental Pathology David Bhella University of Bologna Institute of Virology Via San Giacomo 12, Bologna 40126, MRC Virology Unit Italy Church Street Andrew Carmichael Glasgow, G11 5JR, UK Department of Medicine, University of Cambridge Clinical School, Box 157, Addenbrooke’s Hospital, Hills Karen Biron Road, Cambridge CB2 2QQ, UK Department of Clinical Virology Glaxo Smith Kline Ethel Cesarman 5MooreDrive Pathology Department Research Triangle Park, NC 27709, USA Weill Medical College of Cornell University 1300 York Avenue, Room C410 Michael Boeckh New York, NY 10021, USA Fred Hutchinson Cancer Research Center 1100 Fairview Avenue, N. Bala Chandran Seattle, WA 98109, USA Department of Microbiology and Immunobiology Rosalind Franklin University of Medicine and Catherine M. Bollard Science Center for Cell and Gene Therapy 3333 Green Bay Road Baylor College of Medicine North Chicago 1102 Bates Street, BCM 320 IL 60064, USA Houston, TX 77030, USA William Chang Suresh Boppana Center for Comparative Medicine University of Alabama at Birmingham University of California, Davis 1600 7th Avenue, South. CHB 114 County Road 98 & Hutchison Drive Birmingham, AL 35233, USA Davis, CA 95616, USA

Chris Boshoff Yuan Chang Cancer Research UK Viral Oncology Group Department of Pathology Wolfson Institute for Biomedical Research University of Pittsburgh Cancer Institute University College London Hillman Cancer Center, Research Pavilion, Suite 1.8 Gower Street 5117 Centre Avenue London, WC1E 6BT, UK Pittsburgh, PA 15213-1863, USA

Contributors xi

Duncan Clark Armin Ensser Virology Institut fur¨ Klinische und Molekulare Virologie Royal Free University College Medical School der Friedrich-Alexander Universitat¨ Erlangen-Nurnberg¨ Rowland Hill Street, Schlossgarten 4 London, NW3 2QG, UK D-91054Erlangen Germany

Jeffrey Cohen Thomas Evans Laboratory of Clinical Investigation, NIBRI (Novartis) National Institute of Health 100 Technology Square 10 Center Drive, MSC 1888 Suite 4153 Bldg. 10, Rm 11N228 Cambridge, MA 02139, USA Bethesda, MD, 20892, USA Adam Feire Teresa Compton McArdle Laboratory for Cancer Research, Room 610 NIBRI (Novartis) University of Wisconsin 100 Technology Madison, WI 53706, USA Square, Suite 4153, Cambridge MA 02139, USA Susan Fisher Departments of Stomatology, Anatomy, Pharmaceutical Chemistry and the Biomedical Sciences Graduate Program Lawrence Corey and the Oral Biology Graduate Program Virology Division, Laboratory Medicine University of California, San Francisco University of Washington 513 Parnassus Avenue MC 0512 1100 Fairview Avenue N D3-100 San Francisco, CA 94143, USA Box 358080 Seattle, WA 98109, USA Bernhard Fleckenstein Institut fur¨ Klinische und Molekulare Virologie Blossom Damania der Friedrich-Alexander Universitat¨ Erlangen-Nurnberg¨ Schlossgarten 4 University of North Carolina-Chapel Hill D-91054Erlangen Lineberger Cancer Center, CB#7295 Germany Chapel Hill, NC 27599, USA Karen Fowler Andrew Davison Department of Pediatrics, Epidemiology and Maternal and Institute of Virology Child Health MRC Virology Unit University of Alabama Church Street 1530 3rd Avenue South, CHB 306 Glasgow, G11 5JR, UK Birmingham, AL 35294-0011, USA

Jeppe Friborg Stacey Efstathiou Department of Epidemiology Research Division of Virology, Department of Pathology Statens Serum Institute University of Cambridge, Tennis Court Road 5 Artillerivej, DK-2300 Cambridge, CB2, LQP,UK Copenhagen S, Denmark

Vincent Emery Harvey Friedman Royal Free University College Medical School Department of Medicine Virology Department University of Pennsylvania School of Medicine Rowland Hill Street 502 Johnson Pavilion London, NW3 2PF,UK Philadelphia, PA 19104-6073, USA

xii Contributors

Donald Ganem Julia Hilliard Department of Medicine Georgia State University University of California San Francisco Biology, 424 Science Annex 513 Parnassus Avenue 29 Peachtree Center Avenue San Francisco, CA 94143, USA Atlanta, GA 30303, USA

Anne Gershon Henrik Hjalgrim College of Physicians and Surgeons Department of Epidemiology Research Columbia University Statens Serum Institute Pediatrics, BB4-427 5 Artillerivej, DK-2300 650 W. 168th St. Copenhagen S, Denmark New York, NY 10032, USA

Lauren Hook Benjamin Gewurz Department of Medicine Harvard Medical School University of Pennsylvania School of Medicine 200 Longwood Avenue 502 Johnson Pavilion Department of Pathology Boston, MA, USA Jianhong Hu Department of Molecular Genetics and Microbiology Donald Gilden University of Florida Department of Neurology 1376 Mowry Road, Rm 375E University of Colorado Health Sciences Center Gainesville, FL 32610, USA 4200 E. 9th Ave., B182 Denver, CO 80262, USA Lindsey Hutt-Fletcher Louisiana State University John Gnann, Jr. Health Sciences Center Department of Medicine Feist-Weiller Cancer Center University of Alabama at Birmingham 1501 Kings Highway 845 19th St. S. PO Box 33932 Birmingham, AL 35294, USA Shreveport, LA 71130-3932, USA

Paul Griffiths Michael A. Jarvis Royal Free University College Medical School Vaccine and Gene Therapy Institute Virology Department Oregon Health Sciences University Rowland Hill Street, 3181 S. W. Sam Jackson Park Road London, NW3 2PF,UK Portland, OR 97201, USA

John Hay Aisha Jumaan State University of New York Center for Disease Control Microbiology, Farber Hall, Rm. 138 1600 Clifton Road., MS E-61 3435 Main Street, Bldg. 26 Atlanta, GA 30333, USA Buffalo, NY, 14214, UK Jae Jung Thomas Heineman Division of Tumor Virology St. Louis University Health Sciences Center New England Primate Research Center 3635 Vista Avenue at Grand Blvd. Harvard Medical School PO Box 15250 One Pine Hill Drive St. Louis, MO 63110, USA Southborough, MA 01772, USA

Contributors xiii

George Kemble Thomas Kristie MedImmune, Inc. National Institute of Health 297 North Bernardo Avenue Building – 133 Mt. View, CA 94043, USA 9000 Rockville Pike Bethesda, MD, 20910, USA Shannon Kenney Department of Medical Microbiology and Immunology Chia-chi Ku 1400 University Avenue Department of Pediatrics Madison, WI 53706, USA Stanford University School of Medicine 102 Mason Farm Road, Box 7295 300 Pasteur Drive, Room G312, MC 5208 Chapel Hill, NC 27599-7295, USA Stanford, CA 94305, USA

Julie Kerry Department of Microbiology and Molecular Cell Biology Dimitrios Lagos Eastern Virginia Medical School Cancer Research UK Viral Oncology Group 700 West Olney Road, Lewis Hall #3152 Wolfson Institute for Biomedical Research Norfolk, VA 23507, USA Gower Street University College London Rajiv Khanna WC1E 6BT, UK Australian Centre for Vaccine Development Division of Infectious Diseases and Immunology Sabine Lang Queensland Institute of Medical Research Department of Pathology 300 Herston Road Yale University School of Medicine, LH 304 Herston (Qld) 4006 New Haven, CT 06520, USA Australia

David Kimberlin Ann Leen Department of Pediatrics Baylor College of Medicine University of Alabama at Birmingham Center for Cell and Gene Therapy 1600 7th Avenue South 1102 Bates Street, Suite 760.01 CHB 303 Houston, TX 77030, USA Birmingham, AL 35233, USA Paul Lieberman George Klein The Wistar Institute Microbiology and Tumor Biology Center 3601 Spruce Street Karolinska Institute Philadelphia, PA 19104, USA PO Box 280 S-171, 77 Stockholm, Sweden Fenyong Liu University of California at Berkeley David Koelle School of Public Health Department of Medicine/Infectious Diseases 140 Warren Hall University of Washington Berkeley, CA 94720, USA HMC Virology Division, M.S. 359690 325 9th Avenue Seattle, WA 98104, USA Richard Longnecker Department of Microbiology-Immunology Kaszuhiro Kondo Feinberg School of Medicine Osaka University School of Medicine Northestern University 2-2 Yamada-oka, Suita 303 East Chicago Avenue Osaka 565-9871, Japan Chicago, IL 60611, USA

xiv Contributors

David Lukac Jeffrey Meier UMDN/NJ Medical School Department Internal Medicine Department of Microbiology and Molecular Genetics University of Iowa Int’l Center for Public Health Iowa City, Iowa 52242, USA 225 Warren Street, Room E350T Newark, NJ 07103, USA Mads Melbye Department of Epidemiology Research Louise McCormick Statens Serum Institute Department of Microbiology and Immunology 5 Artillerivej, DK-2300 Emory University School of Medicine Copenhagen S, Denmark 1462 Clifton Road, Suite 429 Atlanta, GA 30322, USA Laura Menotti Department of Experimental Pathology Susan McDonagh University of Bologna University of California San Francisco Via San Giacomo 12, Bologna 4016 513 Parnassus Avenue Italy HSW-604 San Francisco, CA 94143, USA Edward Mocarski Department of Microbiology and Immunology Ravi Mahalingam Emory University School of Medicine Department of Neurology Current address: University of Colorado Health Sciences Center Emory Vaccine Center 4200 East 9th Avenue, Mail Stop B182 1462 Clifton Road, Suite 429 Denver, CO 80262, USA Atlanta, GA 30322, USA Ekaterina Maidji University of California San Francisco Jennifer Moffat 513 Parnassus Avenue SUNY Upstate Medical University HSW-604 Department of Microbiology and Immunology San Francisco, CA 94143, USA 750 E. Adams, Room 2215 Syracuse, NY 13210, USA James M. Markert Department of Surgery University of Alabama at Birmingham Patrick Moore FOT#1050 Molecular Virology Program 1530 3rd Avenue S. University of Pittsburgh Cancer Institute Birmingham, AL 35294-3410, USA Hillman Cancer Center Research Pavilion, Suite 1.8 Jeffrey Martin 5117 Centre Avenue University of California at San Francisco Pttsburgh, PA 15213-1863, USA 185 Berry Street, Suite 5700 San Francisco, CA 94107, USA Andrew Morgan Robert Means University of Bristol Department of Pathology School of Medical Sciences Yale University School of Medicine Department of Pathology and Microbiology 310 Cedar Street LH 315 B University Walk, Clifton, Bristol New Haven, CT 065201, USA BS8 1TD, UK

Contributors xv

Yasuko Mori Christopher Preston Department of Microbiology Medical Research Council Virology Unit Osaka University School of Medicine Church Street 2-2 Yamada-oka, Suita Glasgow G11 5JR Osaka, 565-0871, Japan UK

Mark Prichard Denis Moss University of Alabama at Birmingham EBV Biology Laboratory Department of Pediatrics Queensland Institute of Medical 1600 6th Avenue South Research 128 Children’s Harbor Building Post Ofﬁce, Royal Brisbane Hospital Birmingham, AL 35233, USA Brisbane 4029, Australia

Charles Prober Paul Murray Department of Pediatrics and Microbiology and Cancer Research UK Institute for Cancer Studies Immunology University of Birmingham Stanford University School of Medicine Edgbaston, Birmingham 300 Pasteur Drive, G312, MC 5208 B15 2TT, UK Stanford, CA 94305, USA

Frank Neipel Nancy Raab-Traub Institute fur Klinische und Molekulare Virologie University of North Carolina SchloBgarten 4, Lineberger Cancer Center D-91054 Erlangen, Germany 102 Mason Farm Road Jay Nelson Chapel Hill, NC 27599–7295, USA Department of Molecular Microbiology and Immunology Oregon Health Sciences Center Rolf Renne 3181 S.W. Sam Jackson Park Road Department of Molecular Genetics and Microbiology Portland, OR 97201, USA University of Florida 1376 Mowry Road, Rm 361 Gregory Pari Gainesville, FL 32610, USA Department of Microbiology/320 University of Nevada, Reno Bernard Roizman School of Medicine The Marjorie B. Kovler Viral Oncology Laboratories Reno, NV 89557, USA The University of Chicago 910 East 58th Street Lenore Peirera Chicago, IL 60637, USA University of California San Francisco 513 Parnassus Ave. Cliona Rooney HSW-604 Center for Cell and Gene Therapy San Francisco, CA 94143, USA Baylor College of Medicine Philip Pellett 1102 Bates Street, BCM 320 Department of Virology Houston, TX 77030, USA Lerner Research Institute, NN10, Cleveland Clinic Foundation Barry Rouse 9500 Euclid Avenue Department of Microbiology Cleveland, OH 44195, USA College of Veterinary Medicine University of Tennessee Hidde Ploegh 1414 W. Cumberland Avenue Whitehead Institute for Biomedical Research F403 Walters Life Sciences Cambridge, MA 02142, USA Knoxville, TN 37996, USA

xvi Contributors

William Ruyechan Richard Spaete State University of New York MedImmune, Inc. Microbiology, Farber Hall, Rm. 138 297 North Bernardo Avenue 3435 Main Street, Bldg. 26 Mt. View, CA 94043, USA Buffalo, NY, 14214, USA Deborah Spector Rozanne Sandri-Goldin Department of Cellular and Molecular Medicine Department of Microbiology and Molecular Skaggs School of Pharmacy and Pharmacentical Genetics Sciences, Center for Molecular Genetics College of Medicine University of California San Diego University of California at Irvine 9500 Gilman Drive, MC 0366 C135 Medical Sciences Building La Jolla, CA 92093–0712, USA Irvine, CA, 92697, USA Mark Stinski University of Iowa Thomas Schulz Department of Microbiology Institute fur Virologie, OE 5230 University of Iowa Medizinische Hochschule Hannover Iowa City, Iowa 52242, USA Carl-Neuberg-Str. 1 D-30625 Hannover Takako Tabata Germany University of California San Francisco 513 Parnassus Avenue Jane Seward HSW-604 Centers for Disease Control San Francisco, CA 94143, USA 1600 Clifton Road Atlanta, GA 30333, USA Brunella Taddeo The Marjorie B. Kovler Viral Oncology Labs. Uluhan Sili Ph.D. The University of Chicago Center for Cell and Gene Therapy 910 East 58th Street Baylor College of Medicine Chicago, IL 60637, USA 1102 Bates Street Frank Tufaro Houston, TX 77030, USA Allera Health Products, Inc. 360 Central Avenue, Suite 1560 J. H. Sinclair St. Petersburg, FL 33701, USA Department of Medicine, University of Cambridge Clinical School, Box 157, Addenbrooke’s Hospital, Hills Jatin Vyas Road, 55 First St. GRJ 504 Cambridge CB2 2QQ, UK Massachusetts General Hospital Division of Infections Diseases Patrick Sissons Boston, MA 02114, USA Department of Medicine, University of Cambridge Clinical School Anna Wald Box 157 Virology Research Clinic Aldenbrooke’s Hospital, Hills Road 600 Broadway, Suite 400 Cambridge, CB2 2QQ, UK Seattle, WA 98122, USA

Marvin Sommer Fu-Zhang Wang Department of Pediatrics Cornell University Stanford University School of Medicine Department of Microbiology & Immunology 300 Pasteur Drive, Room G312, MC 5208 C5169 Veterinary Education Ctr. Stanford, CA 94305, USA Ithaca, NY 14853, USA

Contributors xvii

Elizabeth White Lawrence Young Department of Cellular and Molecular Medicine Cancer Research UK Institute for Cancer Studies Skaggs School of Pharmacy and Pharmacentical University of Birmingham Sciences Center for Molecular Genetic and Division of Edgbaston, Birmingham Biological Science B15 2TT, UK University of California, San Diego 9500 Gilman Drive, MC 0366 Yan Yuan La Jolla, CA 92095-0712, USA University of Pennsylvania School of Dental Medicine Richard Whitley 3451 Walnut Street Department of Pediatrics 248 Levy/6002 University of Alabama at Birmingham Philadelphia, PA 19104, USA 1600 7th Avenue, S. CHB 303 Birmingham, AL 35233, USA Leigh Zerboni Department of Pediatrics Mark Wills Stanford University School of Medicine Department of Medicine, University of Cambridge 300 Pasteur Drive, Room G312, MC 5208 Clinical School, Box 157, Addenbrooke’s Hospital, Hills Stanford, CA 94305, USA Road, Cambridge, CB2 2QQ, UK Hong Zhou Mary K. Wloch Department of Pathology and Laboratory Vical Incorporated Medicine 10390 Paciﬁc Center Ct. University of Texas San Diego, CA 92121, USA Houston Medical School Houston, TX 77030, USA Koichi Yamanishi Department of Microbiology Osaka University School of Medicine 2-2 Yamada-oka, Suita Osaka, 565-0871, Japan

Preface

Diseases caused by the human herpesviruses were recognized by the earliest practitioners of medicine. Hip- pocrates, Celsus, Herodotus, Galen, Avicenna and others described cutaneous lesions typical of infections caused by herpes simplex viruses (HSV) 1 and 2, and varicella-zoster virus (VZV). ‘Herpes,’ the family name of these viruses, is traced to the Greek term for lesions that appeared to creep or crawl over the skin. Among the duties of John Astruc, physician to King Louis XIV, was to understand the diseases of French prostitutes, in Latin, the ‘Puellae publicae’, which led to his description of herpes genitalis. Distinguish- ing between genital herpes and syphilis was an obvious concern in this social context as it is now. The modern scientific investigation of HSV can be dated to the work of Gruter, who first isolated the virus and demonstrated its serial transmission in rabbits. During the 19th century, experiments in human subjects showed that HSV and VZV could be transmitted from fluid recovered from HSV and VZV lesions. Demonstrating that Koch’sposulates were ful- filled was important but arguably the truly revolutionary discovery about the herpesviruses was made by Andrews and Carmichael in the 1930s who showed that recurrent herpeslabialisoccurredonlyinadultswhoalreadyhadneu- tralizing antibodies against HSV. Since our modern understanding of all of the human herpesviruses revolves around latency and reactivation as established facts of their biology, it is important to remember that these concepts are far from obvious and to appreciate the creative insights of Doerr who proposed that recurrent HSV was not an exoge- nous infection but resulted from stimuli to the cell that caused the endogenous production of a virus-like agent and of Burnet and Williams who perfected the notion that HSV persists for life and “remains for the most part latent; but under the stimulus of trauma, fever, and so forth it may at any time be called into activity and provoke a visible her- petic lesion.”

xix

xx Preface

Although their relationships to HSV and VZV were by no approaches to clinical diagnosis and the recognition of means appreciated, the more subtle members of the her- the clinical illnesses that result from primary and recur- pesvirus family began to be discovered after an interval rent herpesvirus infections across the age spectrum. All of of many hundreds of years. The first of these was human the herpesviruses have common genes, structures, repli- cytomegalovirus (HCMV), which was initially associated cation strategies and mechanisms of defense against the with human disease through the detection of enlarged cells host response but each virus also has unique properties containingunusualcytoplasmicinclusionsintheurineand that allow it to find its particular ecological refuge. An unex- organs of infants who were born with signs of intrauterine pected outcome of research over the past decade is the find- damage that had been attributed to syphilis. In the early ing that the human herpesviruses have devised many dif- 1950s, HCMV as well as VZV were the first human her- ferentwaystoachievethesamebiologiceffect,asillustrated pesviruses to be isolated in cultured cells. Within a decade, by their unique strategies for down-regulation of major his- Epstein-Barr virus (EBV) particles were found in Burkitt’s tocompatibility complex proteins. Functional similarities lymphoma cells and EBV was shown to be associated with exist among these viruses even when they do not share mononucleosis. By the mid-1990s, three more human her- similar genes or infect similar tissues. Each chapter of the pesviruses, HHV-6A, HHV-6B and HHV-7, which share a book explores these viral themes and variations from the tropism for T lymphocytes, were discovered and the eti- virologic and clinical perspectives. The contributions of ologic agent of the unusual vascular skin tumor called the many distinguished authors highlight the basic science ‘Kaposi’s sarcoma, first described in 1872, was identified as aspects of the field, emphasizing the comparative virology “Kaposi’s sarcoma-asscoiated herpesvirus (KSHV, HHV8). of the human herpesviruses and virus-host cell interac- These four new human herpesviruses were identified dur- tions, and the significant clinical developments, including ing the early years of the human immunodeficiency virus antiviral drugs and vaccines, that are essential for the best (HIV) epidemic because these viruses caused aggressive practice of medicine in the 21st century. The concluding disease in HIV-infected patients or were discovered dur- chapter illustrates how therapies for cancer may emerge ing intensive research on human T cell biology. In each from these advances in basic and clinical research, to cre- instance, discovery of the human herpesviruses paralleled ate a fundamentally new era in the complex history of the technologic progress, illustrated by animal models for HSV, relationship between the human herpesviruses and their cell culture methods for VZV and CMV, the cultivation of hosts. B lymphocytes for the detection of EBV and of T lym- The editors are deeply grateful for the generosity of the phocytes for identification of HHV-6 and 7, and differen- authors who have shared their comprehensive knowledge tial nucleic acid detection for revealing the existence of of the human herpesviruses. We hope that this book will HHV8. serve as a resource for investigators and physicians, and Molecular genetics methods demonstrate that the most importantly, that it will motivate a new generation human herpesviruses share a common ancestor. However, of students and trainees to address the many unresolved each virus has evolved to occupy a particular niche during questions about these herpesviruses as agents of human millions of years of co-evolution with their primate, and disease. Since the genomes of all of these viruses have been eventually human, host. Understanding the nuances of the sequenced, it is obvious that many genes exist for which adaptive strategies that have allowed all of these viruses to functions have not been identified and we now under- be transmitted efficiently and to persist so successfully in stand that most herpesviral proteins can be expected to the human population, and often in the same individual, have multiple functions. Basic research on the human her- constitutesafascinatingenterprise.Atthesametime,infec- pesvirusesalsorevealsfundamentalfactsabouthumancel- tions caused by these ubiquitous viruses create a substan- lular biology, including surface receptors, metabolic path- tialglobalburdenofdiseaseaffectinghealthyandimmuno- ways, cell survival mechanisms, malignant transforma- compromised patients and among people living in devel- tion as well as innate antiviral defenses. In the clinical oped and developing countries. Because of their serious realm, every improvement in diagnostic methods expands and potentially life-threatening consequences, the human the spectrum of clinical disorders that are recognized as herpesviruses are medically important targets for basic and being caused by these viruses. Clinical interventions exist clinical research. that could not have been imagined fifty years ago but the The goal of this book is to describe the remarkable recent need for better therapeutic and preventive measures has progress towards elucidating the basic and clinical virol- become even more apparent as the burden of herpesvirus ogy of these human pathogens, in conjunction with a sum- disease is defined with precision. Given that four human mary of the many new insights about their epidemiology, herpesviruses have been discovered in the past 15 years, mechanisms of pathogenesis and immune control, are there others?