Viral Pathogenesis and Immunity This page intentionally left blank Viral Pathogenesis and Immunity Second edition Neal Nathanson Departments of Microbiology and Neurology University of Pennsylvania Medical Center Philadelphia USA Co-authors Rafi Ahmed Christine A Biron Margo A Brinton Francisco Gonzalez–Scarano Diane E Griffin Kathryn V Holmes Frederick A Murphy Julie Overbaugh Douglas D Richman Erle S Robertson Harriet L Robinson AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 84 Theobald’s Road, London WC1X 8RR, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, California 92101-4495, USA First edition 2002 published by Lippincott Williams & Wilkins Second edition 2007 Copyright © 2007 Elsevier Ltd All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (ϩ44) (0) 1865 843830; fax (ϩ44) (0) 1865 853333; email: permissions@elsevier.com Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this title is available from the Library of Congress ISBN–13: 978-0-12-369464-5 ISBN–10: 0-12-369464-7 For information on all Academic Press publications visit our web site at http://books.elsevier.com Illustrations by Wendy Beth Jackelow, MFA, CMI, Medical & Scientific Illustration, Staten Island, NY, USA Typeset by Charon Tec Ltd (A Macmillan Company), Chennai, India www.charontec.com Printed and bound in Italy 07 08 09 10 11 10 Contents List of Co-authors vii Preface ix Introduction xi Part I Essentials of Viral Pathogenesis 1 Historical Roots Neal Nathanson and Frederick A Murphy The Sequential Steps in Viral Infection Neal Nathanson and Frederick A Murphy 14 Cellular Receptors and Viral Tropism Neal Nathanson and Kathryn V Holmes 27 Virus–Cell Interactions Neal Nathanson and Diane E Griffin 41 Part II Host Responses to Viral Infection 57 Innate Immunity Neal Nathanson and Christine A Biron 59 Immune Responses to Viral Infection Neal Nathanson and Rafi Ahmed 72 Virus-Induced Immunopathology Neal Nathanson and Rafi Ahmed 88 Virus-Induced Immunosuppression Neal Nathanson and Diane E Griffin 99 Part III Virus–Host Interactions Viral Virulence Neal Nathanson and Francisco Gonzalez-Scarano 10 Viral Persistence Neal Nathanson and Francisco Gonzalez-Scarano 130 11 Viral Oncogenesis: Retroviruses Neal Nathanson and Harriet L Robinson 146 12 Viral Oncogenesis: DNA Viruses Neal Nathanson and Erle S Robertson 158 13 Host Susceptibility to Viral Diseases Neal Nathanson and Margo A Brinton 174 14 HIV, SIV and the Pathogenesis of AIDS Neal Nathanson and Julie Overbaugh 185 Part IV Ecology and Control of Viral Infections 201 15 Emerging Viral Diseases Neal Nathanson and Frederick A Murphy 203 16 Antiviral Therapy Neal Nathanson and Douglas D Richman 221 17 Viral Vaccines Neal Nathanson and Harriet L Robinson 234 Glossary and Abbreviations 253 Index 259 111 113 v List of Co-authors Rafi Ahmed Emory University School of Medicine Emory Vaccine Center and Department of Microbiology and Immunology Atlanta GA Christine A Biron Brown University Division of Biology and Medicine Department of Molecular Microbiology and Immunology Providence RI Margo A Brinton Georgia State University Department of Biology Atlanta GA Francisco Gonzalez–Scarano University of Pennsylvania Medical Center Department of Neurology Philadelphia PA Diane Griffin The Johns Hopkins University Bloomberg School of Public Health Department of Molecular Microbiology and Immunology Baltimore MD Frederick A Murphy The University of Texas Medical Branch Department of Pathology Galveston TX Neal Nathanson University of Pennsylvania Medical Center Departments of Microbiology and Neurology Philadelphia PA Julie Overbaugh Fred Hutchinson Cancer Research Center Human Biology Division Seattle WA Douglas Richman VA San Diego Healthcare System and Departments of Pathology and Medicine La Jolla CA Erle Robertson University of Pennsylvania School of Medicine Department of Microbiology Philadelphia PA Harriet L Robinson Emory University Yerkes National Primate Center Department of Microbiology and Immunology Atlanta GA Kathryn V Holmes University of Colorado Health Sciences Center Department of Microbiology Aurora CO vii Preface Infectious disease is one of the few genuine adventures left in the world The dragons are all dead and the lance grows rusty in the chimney corner About the only sporting proposition that remains unimpaired by the relentless domestication of a once free-living human species is the war against those ferocious little fellow creatures, which lurk in the dark corners and stalk us in the bodies of rats, mice and all kinds of domestic animals; which fly and crawl with the insects, and waylay us in our food and drink and even in our love Hans Zinsser, Rats, Lice and History, 1935 To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the cause of disease these are our ambitions William Osler This book is the direct offspring of Viral Pathogenesis, published in 1997 Having read several drafts of all the chapters in Viral Pathogenesis, it was clear that the large book contained a wealth of information, but that it was unsuited for readers who desired an introduction to the topic From that observation sprang the plan for a short version that could be used as an introductory text or for self-education An introductory text clearly benefits from the coherence provided by a single author, but suffers from the finite expertise of any single researcher Therefore, a compromise was devised, in which each chapter was coauthored by an expert in the specific area under consideration This strategy was facilitated by the successful collaborations that had been developed during the preparation of Viral Pathogenesis The text includes references published through to June, 2006 I would like to acknowledge the contributions of the co-authors Their advice and expertise has been essential to the planning and execution of this undertaking and it has been a continual pleasure to work with them They have provided extremely cogent suggestions that have given the book an enhanced level of authority that could not otherwise have been achieved Lisa Tickner and the staff at Academic Press, London, have been an ongoing source of support both because of their enthusiasm for this book and their highly professional expertise in all phases of the project Wendy Jackelow provided the outstanding illustrations rendered from a wide variety of often primitive sketches Neal Nathanson Philadelphia ix Introduction Viral Pathogenesis and Immunity treats all aspects of infection of the animal host, including the sequence of events from entry to shedding, the clearance or persistence of the virus, the immune response of the host and the subsequent occurrence of disease Particular attention is focused on mechanisms that explain the complex interaction between parasite and host This book is designed to provide an introductory overview of viral pathogenesis in a format which will be easy for the reader to absorb without recourse to additional information Principles are emphasized and no attempt is made to provide a virus-by-virus or disease-bydisease compendium, since these are already available in texts of microbiology and infectious diseases Examples are given to illustrate the principles but they are representative not encyclopedic By keeping to essentials, it is hoped to provide a coherent introduction in a brief compass, leaving the reader to acquire more detailed information from well-documented comprehensive texts It is assumed that the reader knows the fundamentals of virology, including the structure of viruses, the organization of their genomes, the basic steps in viral replication, assembly and release In addition, a basic background in cell biology, immunology and pathology will be useful Students who have taken an introductory course in microbiology will have acquired this background and should be well equipped to use this book For those who wish to review these essentials, many excellent texts are available and some outstanding ones are noted below In addition, at the end of each chapter some selected references are provided for readers who wish to delve more deeply into the subject matter or to read a few of the classical original contributions to the field Viral Pathogenesis and Immunity is divided into four parts Part I, Essentials of viral pathogenesis, acquaints the reader with the sequential events in viral infections, the dissemination of virus in the host and the variety of cellular responses to infection Part II, Host responses to viral infection, describes the non-specific and specific immune responses to infection, including the immunopathological and immunosuppressive consequences of infection Part III, Virus–host interactions, deals with virus virulence, virus persistence, virus-induced oncogenesis and the determinants of host susceptibility Part IV, Ecology and control of viral infections, applies the principles of pathogenesis to emergence, treatment and prevention of infection This organization permits readers to select those subjects of particular interest to them, depending upon their background, goals and available time Thus, it would be possible to base an abbreviated introduction to the subject upon Parts I and III alone, particularly for readers with some background in immunology BACKGROUND READING Abbas AK, Lichtman AH Cellular and Molecular Immunology, 5th edn, Saunders, Philadelphia, 2003 Selected chapters will provide a thorough and clear introduction for readers who have not taken a course in immunology Brooks GF, Butel JS, Morse SA Jawetz, Melnick and Adelberg’s Medical Microbiology, 23rd edn, Lange Medical Books/McGraw-Hill, New York, 2004 Basic chapters on properties of viruses and on immunology will provide sufficient background for readers who have not taken a course in microbiology or immunology Janeway CA Jr, Travers P, Walpot M, Shlomchik MJ Immunobiology, 6th edn, Garland Science, New York, 2005 An alternative introductory immunology text FURTHER READING (GENERAL REFERENCES) Flint SJ, Enquist LW, Racaniello VR, Skalka AM Principles of virology, 2nd edn, ASM Press, Washington, DC, 2004 An excellent detailed virology text Knipe DM, Howley PM (eds) Fields’ Virology, 5th edn, Lippincott Williams and Wilkins, Philadelphia, 2007 This exhaustive reference provides definitive information about basic virology and about individual viruses and virus families Richman DD, Whitley RJ, Hayden FG (eds) Clinical virology, 2nd edn, ASM Press, Washington, DC, 2002 This authoritative reference describes viral diseases, supplemented with much basic background information xi This page intentionally left blank 252 Chapter 17 • Viral Vaccines Nishimura Y, Igarashi T, Haigwood N et al Determination of a statistically valid neutralization titer in plasma that confers protection against Simian-Human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies Journal of Virology 2002, 76: 2123–2130 Nyambi PN, Nkengasong J, Lewi P et al Multivariate analysis of human immunodeficiency virus type neutralization data Journal of Virology 1996, 70: 6235–6243 Ogra PL, Karzon DT, Righthand F, MacGillivray M Immunoglobulin response in serum and secretions after immunization with live and inactivated poliovaccine and natural infection New England Journal of Medicine 1968, 279: 893–900 Otten RA, Ellenberger DL, Adams DR et al Identification of a window period for susceptibility to dual infection with two distinct human immunodeficiency virus type isolates in a Macaca nemestrina (pig-tailed macaque) model Journal of Infectious Diseases 1999, 180: 673–684 Ourmanov I, Brown CR, Moss B et al Comparative efficacy of recombinant modified vaccinia virus Ankara expressing simian immunodeficiency virus (SIV) Gag-pol and or Env in macaques challenged with pathogenic SIV Journal of Virology 2000, 74: 2740–2751 Richman DD, Wrin T, Little SJ, Petropoulos CJ Rapid evolution of the neutralizing antibody response to HIV type infection Proceedings of the National Academy of Sciences 2003, 100: 4144–4149 Sabin AB Properties and behavior of orally administered attenuated poliovirus vaccine Journal of the American Medical Association 1957, 164: 1216–1223 Sabin AB, Alvarez MR, Amezquita JA et al Effects of rapid mass immunization of a population with live, oral poliovirus vaccine under conditions of massive enteric infection with other viruses, in Second international conference on live poliovirus vaccines, Scientific Publication 50, WHO, Geneva, 1960 Sabin AB, Hennessen WA, Winsser J Studies on variants of poliomyelitis virus Journal of Experimental Medicine 1954, 99: 551–576 Salinas B, Perez Schael I, Linhares AC et al Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine RIX4414: a randomized, placebo-controlled trial in Latin American infants Pediatric Infectious Diseases Journal 2005, 24: 807–816 Sawyer WA, Meyer KF, Eaton MD, Bauer JH, Putnam P, Schwentker FF Jaundice in army personnel in the western region of the United States and its relation to vaccination against yellow fever American Journal of Hygiene 1944, 39: 337–387 Schmitz J, Kuroda M, Santra S et al Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes Science 1999, 283: 857–860 Schmitz JE, Johnson RP, McClure HM et al Effect of CD8+ lymphocyte depletion on virus containment after simian immunodeficiency virus SIVmac251 challenge of live attenuated SIVmac239∆ 3-vaccinated rhesus macaques Journal of Virology 2005, 79: 8131–8141 Seaman JS, Xu L, Beaudry K, Martin KL et al Multiclade human immunodeficiency virus type envelope immunogens elicit broad cellular and humoral immunity in rhesus monkeys Journal of Virology 2005, 79: 2956–2963 Shibata RR, Igarashi T, Haigwood N et al Neutralizing antibody directed against the HIV-1 envelope glycoprotein can completely blocks HIV-1/SIV chimeric virus infection of macaque monkeys Nature Medicine 1999, 5: 204–210 Sikes RK, Cleary WF, Koprowski H, Wiktor TJ, Kaplan MM Effective protection of monkeys against death from street virus by postexposure administration of tissue-culture rabies vaccine Bulletin of the World Health Organization 1971, 45: 10 Valtanen S, Roivainen M, Piirainen L, Stenvik M, Hovi T Poliovirus – specific intestinal antibody responses coincide with decline of poliovirus excretion Journal of Infectious Diseases 2000, 182: 1–5 Villa L, Costa RLR, Petta CA et al Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomized double-blind placebocontrolled multicentre phase II efficacy trial Lancet Oncology 2005, 6: 271–278 Watkins D Immune responses that successfully control AIDS virus replication Conference on retroviruses and opportunistic infections, 2006, presentation number 180 Wille-Reece U, Flynn BJ, Lore K et al HIV gag protein conjugated to a toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates Proceedings of the National Academy of Sciences 2005, 102: 15190–15194 Whittle HC, Ariyoshi K, Rowland-Jones S HIV-2 and T cell recognition Current Opinion in Immunology 1998, 10: 382–387 Wiktor TJ Cell-mediated immunity and postexposure protection from rabies by inactivated vaccines of tissue culture origin Developmental Biological Standardization 1978, 40: 255–265 Xu ZY, Liu CB, Francis DP et al Prevention of perinatal acquisition of hepatitis B carriage using vaccine: preliminary report of a randomized double-blind placebo-controlled and comparative trial Pediatrics 1985, 76: 713–718 Glossary and Abbreviations αvβ6 integrin chains α-herpesviruses herpesviruses are classified as alpha, beta or gamma, based on their cellular tropism A2G an inbred mouse strain AAV adeno-associated virus, a parvovirus that depends upon adenovirus as a ‘helper’ ACE2 angiotensin-converting enzyme ADCC antibody-dependent cellular cytolysis ADV Aleutian disease virus AIDS acquired immunodeficiency syndrome A/J an inbred mouse strain Aleutian disease a disease caused by a parvovirus that is particularly pronounced in the Aleutian strain of mink ALL acute lymphatic leukemia ALT alanine transaminase, a liver enzyme whose level in the serum reflects liver function ALV avian leukosis virus ALV-A avian leukosis virus A amphotropic a class of murine leukemia viruses that will infect cells from mice and other species Anterograde in the context of neurons, away from the cell body and perinuclear region Anti-HBs antibody against HBs antigen AP-1 activating protein 1, a transcriptional activation complex of proteins AP-2 adapter complex that recruits transmembrane proteins to clathrin-coated pits APC adenomatosis polyposis coli APCs antigen-presenting cells APOBEC apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like, a family of cytidine deaminases Apoptosis programmed cell death, in contrast to necrosis Arboviruses arthropod-borne viruses that are transmitted by an insect vector to a vertebrate host ASC antibody-secreting cell ASLV avian sarcoma leukemia virus ASV avian sarcoma virus ATL acute T cell leukemia Av01 an attenuated mutant rabiesvirus selected by a neutralizing monoclonal antibody B19 designation of a human parvovirus that infects erythrocytes B8R a poxvirus protein homologous to the IFNγR B cell lymphocyte that has matured in bone marrow BALB/c an inbred mouse strain Bcl-2 anti-apoptotic molecule Bgp1 biliary glycoprotein 1, a cellular membrane protein that also serves as a receptor for mouse hepatitis virus BHK-21 a continuous line of baby hamster kidney cells BK polyomavirus a human polyoma virus, named after a patient from whom it was isolated BLV bovine leukemia virus BrdU bromodeoxyuridine, a nucleotide used to label cells C3, C1q, C4b complement proteins C4b a complement protein, an intermediary in the complement cascade C4b-BP plasma protein that binds C4b CA capsid protein of retroviruses Carbolic acid dilute phenol, an antiseptic Carcinoma cancer CAT cationic amino acid transporter CAT1 cationic amino acid transporter CC cysteine-cysteine chemokines CC chemokines chemokines with a cysteine-cysteine motif CCR5 a chemokine receptor that also serves as a co-receptor for HIV CD4 cluster of differentiation 4, a cell surface marker defined by anticellular antibodies, used to define helper T lymphocytes CD8 cluster of differentiation 8, a cell surface marker defined by anticellular antibodies, used to define effector T lymphocytes CD11a adhesion molecule CD25 component of IL-2 receptor CD27 TNF receptor superfamily CD43 adhesion molecule CD44 adhesion molecule CD46 receptor for measles virus CD62L lymph node homing receptor CD69 early activation marker CD127 IL-7 receptor α chain CDK cyclin-dependent kinase CDV canine distemper virus CEACAM carcinoembryonic antigen-related cell adhesion molecule CEV cell-associated enveloped poxvirus CIN cervical intraepithelial neoplasia CMV cytomegalovirus, a γ-herpesvirus c-myc cellular myoclastosis proto-oncogene, a transcription factor CNS central nervous system Colchicine a drug that can block fast axoplasmic transport in neuronal processes Complement fixing antibody antibodies that are capable of binding complement through the Fc domain on the antibody molecule Condyloma wart Coronaviridae a family of positive-stranded RNA viruses CoV coronavirus CpG motifs unmethylated DNA sequences that are recognized by TLR9, inducing innate immune responses CPV canine parvovirus 253 Copyright © 2007 Elsevier Ltd All rights of reproduction in any form reserved 254 Glossary and Abbreviations CR1, conserved region and 2, in adenovirus E1A and HPV E7 proteins CREB CRE binding motif; CRE cAMP responsive element; cAMP cyclic adenosine monophosphate CRPV cottontail rabbit papilloma virus CTAR C-terminal activator regions and CTL cytolytic T cells, lymphocytes capable of lysing target cells on an antigen-specific basis Cupping therapeutic bleeding CVDPV circulating vaccine-derived poliovirus CVS challenge virus standard, a brain passaged highly neurovirulent strain of rabies virus CXC chemokines chemokines with a cysteineX-cysteine motif CXCR4 4th receptor for CXC chemokines ∆32 mutation a 32 base pair deletion in the CCR5 gene that results in lack of expression of the CCR5 protein on the cell surface DC dendritic cell Dendritic cells specialized macrophages found in skin and lymphoid tissues, that are ‘professional’ antigen presenting cells DHF/DSS dengue hemorrhagic fever/dengue shock syndrome DTH delayed-type hypersensitivity Dysplasia pre-cancerous change in cell phenotype E envelope protein E, L early and late genetic regions E1A, E1B, E3 two ‘early’ proteins of adenovirus E2 one of the envelope proteins of Sindbis virus, an alphavirus E2F family of related transcription factors EBNA Epstein-Barr nuclear antigen EBV Epstein-Barr virus ecotropic a class of murine leukemia viruses that will only infect mouse cells EGF epidermal growth factor EIAV equine infectious anemia virus, an equine lentivirus that causes a characteristic acute anemia EIF eukaryotic Initiation Factor ELISA enzyme-linked immunosorbent assay Elispot an assay for functional CD8 cells that measures the production and secretion of cytokines such as IFNα in response to a specific antigen endogenous applied to retroviral sequences that exist as sequences within germline DNA enhancer a DNA sequence that enhances transcription by binding cellular proteins that convert cellular DNA from a ‘condensed’ state associated with histones to an ‘open’ state that is accessible to RNA polymerases env envelope gene of retroviruses ER endoplasmic reticulum ErbB-1 cellular growth factor ESCRT-1, -2, -3 endosomal sorting complex required for transport ev endogenous chicken virus, retroviral sequences in the chicken genome exogenous applied to retroviruses that circulate as replication competent viruses and are transmitted as an infection from host to host F1 progeny from a cross between two parental strains of an organism FACS fluorescent activated cell sorter FcγIIIR Fcγreceptor FcR receptor for the Fc domain of immunoglobulin molecules FeLV-B feline leukemia virus B FeSV feline sarcoma virus Flv gene that influences susceptibility to flaviviruses FMD foot-and-mouth disease virus FMR Friend, Maloney, Rauscher group of murine leukemia viruses F-MuLV Friend murine leukemia virus Fomites microbiologically-contaminated materials that transmit infection FIV feline immunodeficiency virus, a lentivirus of cats FPV feline panleukopenia virus gag group antigen(s) of retroviruses gag gene the gene that encodes the major internal structural proteins of retroviruses GALT gut-associated lymphoid tissue GALV gibbon ape leukemia virus gB, gC, gD, gE, gI, gC glycoproteins of herpes simplex virus GH growth hormone G-MuLV Gross murine leukemia virus gp41 HIV transmembrane (TM) envelope protein gp120 HIV surface (SU) envelope protein gp160 HIV envelope glycoproteins prior to cleavage into gp41 and gp120 GPCR G-protein-coupled receptor Gross/AKR Gross subgroup of murine leukemia viruses GSK glycogen synthase kinase GTPase guanosine triphosphatase H1N1 hemagglutin 1, neuraminidase 1, terminology indicating antigenic classification of influenza viruses H5N2 designation for the hemagglutinin and neuraminidase of influenza virus, based on serotype classification of human and animal influenza viruses HA hemagglutinin of influenza virus, consisting of two peptides, HA1 and HA2 HAART highly active antiretroviral therapy HAV hepatitis A virus HAVcr-1 HAV cellular receptor HBcAg the core antigen of HBV HBIG hepatitis B immune globulin HBs hepatitis B surface antigen, the viral envelope protein HBV hepatitis B virus HCV hepatitis C virus Heparan sulfate a glycosaminoglycan (complex carbohydrate) 255 Glossary and Abbreviations HER hemorrhagic encephalopathy of rats herd immunity protection conferred on unimmunized members of a partially vaccinated population because virus transmission is reduced in the immunized members of the group HHV8 human herpesvirus 8, also called Kaposi’s sarcoma herpesvirus HIV-1, HIV-2 the two major types of human immunodeficiency virus HLA human leukocyte antigen HPCs hematopoietic precursor cells HPV human papillomavirus, a cause of cervical carcinoma HR heptad repeat HSV herpes simplex virus HTLV-I human T lymphocyte tropic virus type I HVEM herpesvirus entry mediator, member of the TNF receptor family of proteins ic intracerebral ICAM intercellular adhesion molecule ICE interleukin converting enzyme ICP’n’ infected cell protein, a term used to designate individual proteins of HSV IE immediate early, E (early) and L (late) genes of HSV; a listing of viral genes according to the time of their expression during replication IEV intracellular enveloped poxvirus IFN interferon IFNαRKO interferon α/β knockout mice IFNγ interferon gamma, or immune interferon IFNγR cellular receptor for IFNγ Ig immunoglobulin IgA immunoglobulin A, an immunoglobulin that is secreted by B cells found in mucosal tissues IgG immunoglobulin, once called gamma globulin IL-1 interleukin Il-2 interleukin (also called T cell growth factor) Il-4 interleukin IL-Rγc interleukin receptor γ chain immortalized cell line cell line that can be maintained indefinitely in culture, in contrast to non-transformed cell lines that can be maintained for about 60 subcultures before they lose viability IN integrase enzyme of retroviruses INOS inducible nitric oxide synthase In situ PCR a method for the histochemical identification of specific nucleic acids using sequence amplification followed by in situ hybridization IntDCs interstitial DCs IPV inactivated poliovirus IRES internal ribosome entry site ISVP infectious subvirion particle of reovirus JAK the Janus tyrosine kinase JC polyomavirus a human polyoma virus, named after a patient from whom it was isolated JNK Jun N-terminal kinase KIR killer inhibiting receptor, receptors in NK cells that inhibit perforin-mediated killing ‘Knockout’ mice mice in which a specific gene has been inactivated using a method that involves homologous DNA recombination in embryonic stem cells KS Kaposi’s sarcoma, a skin cancer KSHV Kaposi’s sarcoma herpes virus, the cause of KS, also called HHV8 L929 cells a murine cell line LANA latency-associated nuclear antigen LANA-1 latency-associated nuclear antigen-1 LAT latency-associated transcript, a term used for RNA transcripts of the HSV genome that are produced during latency LC Langerhans cell LCMV lymphocytic choriomeningitis virus, an arenavirus LD50 50% lethal dose LDA limiting dilution assay, used to quantify CTL precursor or memory cells LDL low density lipoprotein LDV lactic dehydrogenase virus LEF lymphoid enhancing factor LMO2 LIM-only protein 2, a bridging protein in transcription complexes which, if over-expressed, can act as an oncogene LMP latent membrane protein LPS lipopolysaccharide LTR long terminal repeat, a non-coding region at the termini of retroviruses, containing translational start sites, promoter and enhancer elements M2 matrix protein M, N, O main, new, outlier, subgroups of HIV-1 M cells (microfold cells) specialized cells in the epithelium of the intestine that are involved in antigen uptake and viral entry MA matrix protein Macrophages the principal phagocytic cells of the body MALT mucosal associated lymphoid tissue MAR monoclonal antibody resistant, virus selected by growth in the presence of a neutralizing monoclonal antibody MBP myelin basic protein MCFV mink cell focus forming virus MCMV mouse cytomegalovirus MDCs myeloid dendritic cells MDV Marek’s disease virus MHC major histocompatibility complex, a highly polymorphic region of the mammalian genome that encodes proteins important for immune responses MHC class I protein major histocompatibility proteins that are divided into two groups, class I and class II MHV mouse hepatitis virus, a nidovirus MHVR mouse hepatitis virus receptor, with alleles designated Bgp1a and Bgp1b Microtubule intracellular organelle consisting of a tubular structure composed of tubulin proteins; microtubules are polarized, with assembly and disassembly preferentially occurring at the ‘plus’ end of the tubule 256 Glossary and Abbreviations MiRNA micro RNAs, small interfering RNAs produced by cells MLV-A murine leukemia virus A MLV-E murine leukemia virus E Mos Maloney mouse sarcoma, an oncogene MP mousepox MPV mouse polyoma virus MSV murine sarcoma virus MT-2 a continuous cell line of human T lymphocytes in which T cell-adapted HIV-1 strains can be grown MuLV murine leukemia virus, an oncogenic retrovirus of mice MV mixed virus, a neurotropic type strain of poliovirus MVA modified virus Ankara, an attenuated vaccinia virus Mx gene a genetic locus that influences host susceptibility to myxoviruses such as type A influenza virus myc myelocytomatosis, an oncogene MyD88 myeloid differentiation factor 88 NA a continuous cell line derived from a mouse neuroblastoma (nervous system tumor) NC nucleocapsid protein of retroviruses Nectins members of the immunoglobulin superfamily of proteins nef negative factor, so called because it was thought to have a negative effect on the replication of HIV; now known to carry several activities that regulate the interaction between HIV and its host cells NFAT nuclear factor of activated T cells NFκ B nuclear factor κB, a transcriptional activator NK cell natural killer cell NNRTI non-nucleoside reverse transcriptase inhibitor NRTI nucleoside reverse transcriptase inhibitor NYVAC an attenuated vaccinia virus OPV oral poliovirus vaccine (aka Sabin vaccine) p12 a gag protein of retroviruses p15e 15kD envelope protein of some retroviruses p53 a tumor suppressor protein PAMPs pathogen-associated molecular patterns Papilloma wart PBMCs peripheral blood mononuclear cells PCR polymerase chain reaction pCTL precursor cytolytic T lymphocytes, assayed for lytic activity after culturing dilutions of harvested cells in the presence of antigen pDCs plasmacytoid dendritic cells Peyer’s patches lymphoid patches in the lining of the small intestine PFU plaque forming units PI3K phosphoinositide-3-OH kinase PiT inorganic phosphate transporter Pit2 sodium phosphate cotransporter pol polymerase polyprotein of retroviruses, encodes protease, reverse transcriptase, and integrase polytropic also called MCF viruses, a class of murine leukemia viruses that will infect vertebrate cells other than mouse cells and exists only as endogenous sequences in the mouse genome MCF viruses can be ‘rescued’ by recombination with exogenous viruses PR protease enzyme of retroviruses Pr60gag the gag protein encoded by the MAIDS virus, a variant of the normal gag protein pRb retinoblastoma protein PRI designation of a strain of mice, after the Princeton Rockefeller Institute PrM pre-matrix protein promoter a DNA sequence that can bind RNA polymerases and initiate transcription of downstream exons PRRs pattern recognition receptors Pseudorabies virus an α-herpesvirus of pigs PTLD post-transplant lymphoproliferative disease PVR poliovirus receptor ras rat sarcoma, an oncogene RDA representational difference analysis Retrograde in the context of neurons, from periphery towards the cell body Rev regulator of expression of HIV proteins, regulates splicing of viral messages and their transport to cytoplasm RFC/B.5 an attenuated bunyavirus mutant selected by passage in cell culture Rfv-1 a gene that affects recovery from Friend MuLV Rfv-2 a gene that affects recovery from Friend MuLV Rgv-1 a gene that affects recovery from Gross MuLV RHDV rabbit hemorrhagic disease virus RIF Rous interfering factor or resistance-inducing factor, an ALV that interferes with superinfection by a RSV of the same subgroup RIP receptor-interacting protein RISCs RNA-induced silencing complexes RNAi RNA interference RPV rabbit papilloma virus RSV respiratory syncytial virus RSV Rous sarcoma virus RT reverse transcriptase RTA replication and transcription activator RTI reverse transcriptase inhibitor RV194-2 an attenuated mutant rabies virus selected by a neutralizing monoclonal antibody Sarcoma tumor of transformed muscle cells SARS virus severe acute respiratory syndrome Schwann cells cells that form the myelin sheath around neuronal processes of peripheral nerves SeMNPV S exigua multicapsid nucleopolyhedrosis virus fusion protein SHIV simian human immunodeficiency virus SI stimulation index Sindbis virus a member of the togavirus family siRNAs small interfering RNAs SIV simian immunodeficiency virus Skp1p proteosome targetting factor SNV sin nombre virus src sarcoma, an oncogene Src an intracellular kinase, the protein encoded by the src gene 257 Glossary and Abbreviations SRS suppressor of RNA silencing SSPE subacute sclerosing panencephalitis, a chronic progressive fatal infection of humans caused by measles and, rarely, rubella virus STAT signal transducer and activator of transcription Stratum corneum the outermost layer of the epidermis Stratum granulosum the intermediate layer of the epidermis Stratum Malphighii the innermost layer of the epidermis SU surface protein of retroviruses SV5 simian virus SV40 simian virus 40 t1/2 half-life T cell lymphocyte that has matured in the thymus tat transactivator of transcription, an HIV gene that increases transcription of viral DNA TATA a frequently occurring DNA sequence in promoters found upstream of open reading frames tax trans-acting protein in the HTLV-1 group of retroviruses TCD tissue culture dose, adequate to infect a cell culture TCF T cell factor TCL T cell line, a cell line derived from transformed T lymphocytes TCR T cell receptor TgPRV transgenic mice expressing the PVR TH1 CD4ϩ cells secreting IL-2 and IFNγ and inducing cellular immune responses TH2 CD4ϩ cells secreting IL-4 and inducing B lymphocyte immune responses TIR toll-interleukin receptor Thoracic duct the final conduit that carries lymph into the vena cava TLR toll-like receptor TLR3 toll-like receptor a cell-surface molecule that binds dsRNA TLRs toll-like receptors TM transmembrane protein of retroviruses TNF tumor necrosis factor TNFα tumor necrosis factor α, a pro-inflammatory cytokine Tolerance a state of immunological unresponsiveness TRADD tumour-necrosis-factor-receptor-associated death domain TRAF TNF tumor necrosis factor receptor-associated factor transformed cell line an immortalized cell line that shows an oncogenic phenotype evidenced by criteria such as the ability to produce colonies in agar, foci in cell culture and tumors in immunosuppressed mice Trigeminal ganglion the organ containing the cell bodies of the trigeminal nerve fibers Trigeminal nerve one of the cranial nerves that provides sensory innervation to much of the face and that may act as a site for latent HSV genomes TRIM5α tripartite motif 5α Ts temperature sensitive, a viral variant that can replicate at ‘standard’ temperatures such as 37°C, but is restricted at elevated temperatures such as 40°C (where wildtype viruses can usually replicate well) TSH thyroid stimulating hormone TUNEL assay terminal deoxynucleotidyl transferasemediated dUTP nick end-labelling, an assay for apoptosis U3 unique 3’ non-coding sequence in retrovirus genomes U5 unique 5’ non-coding sequence in retrovirus genomes VAP virus attachment protein VCP vaccinia complement control protein, a protein that binds to C4b VEEV Venezuelan equine encephalitis virus, an alphavirus VEGF vascular endothelial growth factor vif virus infection factor, an HIV-1 accessory protein vIL-6 viral interleukin vIRF-1 viral interferon regulatory factor VCP vaccine complement control protein VMV visna maedi virus, an ovine lentivirus that causes interstitial pneumonitis and demyelination VP1 virus protein Vpr virion protein R, an accessory HIV protein that is required for nuclear import of the pre-integration complex in non-dividing cells vpu virion protein U, an HIV accessory protein that enhances virion release from infected cells VZV varicella zoster virus, an α-herpesvirus WHV woodchuck hepatitis virus WNV West Nile virus, a member of the flavivirus family xenotropic a class of murine leukemia viruses that will infect vertebrate cells other than mouse cells This page intentionally left blank Index Actin assembly, 50 Acute infection, 25 clearance, 132, 133 Acute transformation, 149, 151–152 Acyclovir, 231, 232 Adefovir, 230 Adenovirus, 16, 37, 49 apoptosis induction/blocking proteins, 48, 49 exit from host cells, 50, 51 MHC Class I molecule expression down regulation, 46–47, 104, 137, 165 oncogenesis, 158, 165–166 vectors, 160 recombinant vaccine production, 239 Adjuvants, 234, 240 Adult T cell leukemia, 154, 155 Aerosol transmission, 18, 24 Age-specific effects, 131 antibody production, 25 HIV progression to AIDS, 180 host response, 4, persistent infections, 142 susceptibility/resistance, 181–183 virus-induced immunosuppression, 108–109 Agribusiness, spread of infections, 211–212 AIDS see Human immunodeficiency virus (HIV) AIDS-associated lymphoma, 166, 191 Aleutian disease virus, 20, 137 Amantadine, 228 Animal models, 214–215 Antibody, 20, 53, 76–78, 82 assays, 8, 76–77 B cell surface, 73 classes, 78 effector functions, 77 kinetics of response, 78 maturation of response, 83 mucosal immune response, 83, 84 natural, 67 neutralizing activity, 77, 78, 132 production induction, 74–76 reinfection response, 82–83, 84 therapeutic, 227 viral attachment protein blockade, 32 virus-induced immunopathology, 95–96 Antibody-dependent cell-mediated cytolysis, 63, 77, 90 Antigen presentation, 53 Antigen processing, 75 Antigen–antibody (immune) complexes immunopathology, 9, 95, 143 persistent infectivity, 20, 95, 137 Antigen-presenting cells, 61, 62, 73, 74, 75, 76 vaccine immunogen processing, 234, 236, 239, 240 viral infection, 9, 99 lymphocytic choriomeningitis virus, 100 Antigenic variation, 137–139 Antiviral peptides, 223–224 Antiviral therapy, 221–232 antiviral peptides, 223–224 approved drugs, 227–232 cellular protein targets, 225 drug-resistant mutations, 224–225 RNA interference, 222–223 strategies based on pathogenesis, 225–227 therapeutic antibody, 227 viral mutagens, 222 viral proteins, 222 APOBEC3G antiviral protein, 51–52, 68, 188 Apoptosis cytolytic T cell-mediated, 80, 89 p53 regulation, 160 viral blocking proteins, 49 viral induction, 43, 48–49 human immunodeficiency virus, 188, 197 Arboviruses, 16–17, 25, 207–208 Arenaviruses, 24 Attachment, 28–32 host cell response, 43 Attenuated vaccine viruses, 235–238 efficacy, 236–237 safety, 237–238 Attenuation, 114, 115 comparative pathogenicity studies, 119–123 genetic determinants, 123–126 procedures, 116–119 passage in animals, 116 passage in cell culture, 116–117 selection, 117–119 Autoimmunity, virus initiated, 96–97 Avian influenza virus, 205, 209, 210 H5N1 variant, 69, 70, 126, 209 H5N2 variant, 39 virulence, genetic determinants, 126 Avian sarcoma leukosis viruses, 37, 38, 45, 46, 238 genetic determinants of susceptibility, 178 oncogenesis, 154 B cells, 72 antibody production induction, 74–76 attenuated virus stimulation, 236 cytokines release, 75 surface immunoglobulin, 73, 74 viral infection, 19, 20, 21 Epstein-Barr virus, 166, 167, 168 human herpesvirus 8, 169 B virus, 16 Barriers to infection gastrointestinal tract, 18 respiratory tract, 18 skin, 15 Bax, 160 bcl-2, 49, 163 BK polyoma virus, 136, 165 Blood-borne viruses, 14, 24, 25, 189 trancutaneous injection, 16–17 transit to cerebrospinal fluid, 21 Blood–brain barrier, 21, 38, 136, 183 Bovine leukemia virus, 152, 154 BR8, 104 Brain, persistent infections, 136 Bunyaviruses, genetic determinants of virulence, 124–125 Burkitt’s lymphoma, 166, 167–168, 191 C1q, 77, 103 Cancer induction, 155–156 human papillomaviruses, 161, 163 molecular determinants, 155 see also Retroviruses, oncogenesis Canine distemper virus, 143 immunosuppressive actions, 105 Canine parvovirus, 210–211 Carcinoembryonic antigen cellular adhesion molecule 1a (CEACAM1a), 30, 31, 32 Carrier cultures, 131–132 Case:fatality rate, 115, 116 Case:infection ratio, 115, 116 CCR5 human immunodeficiency virus co-receptor function, 43, 48, 186, 187, 189 mutations mediating resistance, 179, 180, 196, 198, 225 mutations slowing HIV progression to AIDS, 180 therapeutic manipulation, 225 West Nile virus host defenses, 179 CD4 human immunodeficiency virus receptor, 28, 29, 30, 101, 107, 121, 186 host cell attachment response, 43, 45 CD4 T cells, 73 CD8 T cell interactions effector function induction, 76 immunopathologic, 90 259 260 Index CD4 T cells (Continued) memory cell induction, 81 cytolytic function, 80 human immunodeficiency virus infection, 17, 21, 101–102, 107, 108, 186, 193, 195 AIDS severity assessment (CD4 cell counts), 115, 190 cell killing, 43, 188 human T lymphocyte tropic virus type infection, 154, 155 lymphocytic choriomeningitis virus functional dysregulation, 100–101 mucosal immune response, 84 simian immunodeficiency virus infection, 189 T cell receptor–MHC Class II molecule interactions, 74–75 TH1 subset, 73, 76 TH2 subset, 73, 74–75, 76 CD8 T cells, 9, 53, 54, 73 α-defensins, 67 cytokines release, 80, 89 cytolytic activity, 73, 74, 80, 89 dendritic cell interactions, 75–76 effector functions, 80–81 induction, 76 ELISPOT assay, 80 human immunodeficiency virus cellular immune response, 188, 192, 197, 249 intracellular cytokine staining, 79–80 kinetics of response, 81, 82 limiting dilution assay, 78–79 memory cells, 81, 101 mucosal immune response, 83, 84 persistent infection with immune tolerance, 134–135 T cell receptor–MHC Class I molecule interactions, 76, 89 tetramer assay, 79 virus-induced immunopathology, 89–95 Cell culture, 7, 8, 214–215 persistent infection models, 131–132 Cell cycle alterations following infection, 49–50 DNA tumor virus activation, 159, 162, 165, 166, 170 retinoblastoma protein regulation, 159–160 Cell-associated viremia, 20–21 Cell-mediated immune response, 75, 78–81, 82, 132 assays, 78–80 human immunodeficiency virus infection, 188, 192 kinetics, 81, 82 virus-induced immunopathology, 89–95 hepatitis B virus, 93–95 lymphocytic choriomeningitis virus, 90–92 respiratory syncytial virus, 92–93 Theiler’s murine encephalomyelitis, 93 Cellular membranes, alterations following infection, 44–47 Cellular response to infection see Host cell alterations Cervical carcinoma, 160–164, 191, 246 Chediak-Higashi syndrome, 63 Chemokine receptors, coreceptor function, 28 Chicken anemia virus, 49 Choroid plexus, 21 Chronic diseases, 11–12, 143, 144, 214 see also Persistent infection Co-receptors, human immunodeficiency virus, 28, 29, 121–122 see also CCR5; CXCR4 Cold adapted variants, 117, 118, 235–236 Complement, 67 cascade blockade by viral proteins, 103, 127 Conjunctival entry, 16 Coronaviruses, 18, 116, 218 Cotton rabbit papillomavirus, 164, 174 Coxsackievirus A24, 16 CXCR4, human immunodeficiency virus co-receptor function, 43, 48, 186, 187 Cyclin-dependent kinases, 159, 160 Cyclins, 159, 160 Cytokines, virus-induced aberrant responses, 104, 127 measles, 106 Cytolysis, 41, 42 Cytolytic T cell assay, Cytomegalovirus, 24, 136, 143, 191 antiviral therapy, 232 host cell transcription modulation, 44, 47 latent infection, 135 Danger hypothesis, 61 Defensins, 66–67, 223, 224 Definitions, Dendritic cells, 15, 17, 60, 61–62, 63, 69, 73, 74 antigen processing, 75 CD8 T cell interactions, 75–76 Fc receptors, 73 viral infection, 99 human immunodeficiency virus, 101, 186, 187, 189 lymphocytic choriomeningitis virus, 100, 105, 109, 123 measles, 100, 106 simian immunodeficiency virus, 189 Dengue virus, 95–96, 207 recombinant vaccine production, 239 Direct host-to-host transmission, 25 DNA tumor viruses, 158–171 human papillomaviruses, 160–164 large DNA viruses, 158 mechanisms of oncogenesis, 159–160 small DNA viruses, 158 DNA vaccines, 239–240 candidate AIDS vaccines, 249, 250 Drug-resistant mutations, 224–225 Ebola virus, 48, 116, 216 Ecologic disruption, spread of new infections, 212 Ectromelia (mousepox), Electron microscopy, 215 ELISPOT assay, 76–77, 78, 80, 192 Emerging diseases, 203–219 agribusiness-related, 211–212 deliberately introduced viruses, 213 ecologic disruption-related, 212 host population susceptibility, 204–205, 206 transportation-related global spread, 211 urban spread, 211 viral virulence, 205 virus classification, 215–216 virus identification, 214–218 xenotransplantation, 214 zoonotic infections, 206–211 Emtricitabine, 230 Endogenous antigen processing pathway, 75 Endothelial cell infection, 21 Enfuvirtide, 222, 231 Enhancer activation, 149 Entecavir, 230 Enteric viruses, 17–18 enterotropic adaptations, 37 shedding, 24 Enterovirus 70, 16 Entry, 15–18 attachment, 28–32 gastrointestinal tract, 17–18 host cell non-immune defenses, 51–52 mechanisms, 32–33 mucous membranes, 15–16, 17 naked capsid viruses, 33, 34 oropharynx, 17–18 respiratory tract, 18, 19 skin, 15–16, 17 transcutaneous injection, 16–17 urogenital tract, 17 virulent/attenuated virus comparisons, 119 env, 147, 151, 153, 154, 185, 249 Environmental survival of shed virus, 24 Enzyme-linked immunosorbent assay (ELISA), 76, 77, 191–192 Epidermal growth factor receptor, 162 Epitopes, 73 molecular mimicry, 97 Epstein-Barr virus, 24, 27, 143, 160, 191 261 Index host chromosome utilization, 50 latent infection, 135, 167 oncogenesis, 166–168 Equine infectious anemia virus, 137, 143 Erythrocyte/erythroblast infection, 20, 21 parvovirus B19, 35 Escape mutants, 32, 137, 138–139, 142, 196, 228, 249 Exit from host cells, 50 Exogenous antigen processing pathway, 75 Famciclovir, 232 Fc receptors, 73, 77, 96 Fecal–oral transmission, 24, 37 Feline immunodeficiency virus, 143 Feline panleukopenia virus, 210 Fenestrated capillaries, 21 Fetal infection retroviruses, 147 rubella, immunosuppressive activity, 107 tolerance induction, 102 Filterable nature, 5–6, 214 Flaviviruses, genetic determinants of susceptibility, 175, 177 Fluorescent activated cell sorting, 79–80, 192 Fluorescent labeling, Flv, 175, 177 Food-borne transmission, 25 Foot-and-mouth disease, 5–6, 211 Friend virus, 134–135 Furin, 126 Fusion, 32, 33, 42, 44, 186 proteins, 36 proteolytic processing, 36–37 Fv1, 177–178 G-protein coupled receptors, 49 gag/gag, 147, 151, 185, 191, 249 Ganciclovir, 232 Gastroenteritis, 17, 215 Gastrointestinal tract barriers to infection, 18 enterotropic viral adaptations, 37 mucosal immune system, 83–84 viral entry, 17–18 viral shedding, 24 Gender-specific susceptibility, 183 Gene therapy, 149, 160 retrovirus vectors, 149, 156 Genital fluids, viral shedding, 24 Genital tract entry, 17 Genome sequencing, Genomic analysis, 10–11 host cell alterations, 47 Gleevec, 225 Globoside, 35 Glycolipid receptors, 30 Glycoprotein receptors, 29–30, 32, 34, 36 Glycosoaminoglycan receptors, 30 Granzymes, 80, 89 Hantavirus pulmonary syndrome, 203–204, 217 Helper (replication-competent) viruses, 9, 147, 151, 152, 154 Hemagglutinin, 32, 33, 37, 205, 209, 210 influenza virus virulence, 126 protease cleavage, 126 viral mutation, 39 Henle-Koch postulates, 5, 216 Heparan sulfate, 30, 32 Hepatitis A, 24, 25 Hepatitis B, 20, 76, 80, 97, 183, 214, 216, 226, 227, 238 antiviral therapy, 229–231 cell-mediated immunopathology, 93–95 genetic determinants of susceptibility, 181 newborn infant infection, 244 tolerance, 182 persistent infection, 26, 88, 131, 133, 134, 142–143, 182, 244 shedding, 23 transgenic mouse model, 94 transmission, 16–17, 18, 24 vaccine, 26 mechanism of protection, 243–245 recombinant protein, 238 Hepatitis C, 17, 76, 104, 214, 216, 226, 227 antiviral therapy, 228–229 genetic determinants of susceptibility, 181 transmission, 24 Hepatitis E, 24, 183 Herpes simplex virus, 15, 19, 23, 143, 191 age-specific susceptibility, 182 antiviral peptides, 223 antiviral therapy, 231, 232 complement cascade blockade, 103 entry pathway, 32–33 host cell receptor interactions, 29, 30 Fc receptors, 127 latent infection, 135, 139–141 activation, 122, 136, 140–141 type 1, 22, 24, 139 type 2, 17, 22, 24, 139, 183 Herpesvirus entry mediator, 33 Herpesviruses, 49, 63, 67 immunomodulatory protein production, 103 latent infection, 135 MHC Class I molecule downregulation, 104 oncogenesis, 158, 166–170 viral polymerase inhibitors, 231–232 virulence determinants, genes of cellular origin, 127 Highly active antiretrovial therapy (HAART), 194, 195, 231 Historical aspects, 3–13 demonstration of viral causal agents, 5–6 early studies, 6–7 innate immunity, 60 molecular biologic methods, 9–10 quantitative studies, recent developments, 10–13 terminology, HLA haplotype, HIV progression to AIDS, 180, 198 Hodgkin’s disease, 166 Host cell alterations, 42, 43–47 cell cycle, 49–50 cell death, 48–49 chromosome utilization for viral replication, 50 genomic analysis, 47 membranes, 44–47 protein synthesis, 44, 45 transcription, 43–44 viral attachment response, 43 viral exit, 50 Host cell defenses, 50–53 immune see Immune response non-immune, 51–53, 188 viral evasion, 51–53 Host range, 27–38, 174 species barrier, 208, 211 Human herpesvirus 8, 49, 160, 168–170, 191, 214, 217–218 Human immunodeficiency virus (HIV), 13, 99, 143, 185–199 acute infection, 190 age-specific susceptibility, 182 AIDS opportunistic infections, 107, 108, 191, 197 AIDS-related neoplasms, 166, 191 Kaposi’s sarcoma see Kaposi’s sarcoma antibody response, 191–192, 249 antigenic variation/escape mutants, 138, 139, 196, 249 antiviral therapy, 194, 195, 222, 224, 225, 230, 231 drug-resistant mutations, 224 multidrug therapy, 225 protease inhibitors, 231 reverse transcriptase inhibitors, 231 attachment, 186, 187 apoptosis induction, 43, 48 attachment protein (gp120), 29, 32, 186, 191, 249 CD4 binding, 186 attenuated variant (Sydney cohort), 247 CCR5 co-receptor, 43, 48, 186, 187, 189 mutations mediating resistance, 179, 180, 196, 198, 225 mutations slowing progression to AIDS, 180 therapeutic manipulation, 225 CD4 receptor, 28, 29, 30, 101, 107, 121, 186 expression reduction following infection, 45 262 Index Human immunodeficiency virus (HIV) (Continued) CD4 T cell infection, 101–102, 193 cellular turnover, 195 counts, disease severity assessment, 115, 190 cell killing, 187–188 cellular host range, 186–187 cellular immune response, 188, 192 co-receptor requirement, 121–122 CXCR4 co-receptor, 186, 187 effect of passage on phenotype, 117 entry pathway, 32, 186, 187 exit from host cells (ESCRT system), 50 HIV-1, 186, 197 clades, 197, 249 HIV-2, 186, 191, 197, 248 host cell cycle arrest, 49–50 host cell receptor interactions, 28–29, 30 immunogenic proteins, 191 epitopes, 192 immunosuppressive mechanism, 76, 107–108, 197–198 intrinsic cellular defenses, 188 APOBEC3G antiviral protein, 51–52, 53, 68, 188 RNA interference, 53 TRIM5α, 51, 188 Vif accessory protein, 51–52, 53, 188 latent infection, 196–197 subclinical phase, 190 virus setpoint, 190 virus turnover, 193–194 local immunity with exposed seronegative (ESN) status, 179–180 long terminal repeats, 50 long-term non-progressors, 190–191 measles virus interaction, 50 MHC Class I molecule downregulation, 104 Nef gene/Nef protein, 45–46, 47, 186 origins, 210 persistent infection, 26, 32, 133, 194, 231, 248 phenotypic changes, 196 progression to AIDS, 190 HLA haplotype associations, 180, 198 host determinants, 180 reinfection (superinfection), 248–249 immune response, 192–193 replication, 187 shedding, 23 spread of infection, 189 structure, 186 subgroups, 186 susceptibility, genetic determinants, 174, 179–180, 196, 198 transmission, 17, 18, 24, 25, 189 gender-related differences, 25, 183 tropism, 121–122, 186–187 vaccine development, 247–250 viral setpoint, 190, 192, 193, 248 viral variation, 195–197 viremia, 21, 190–191, 192 HAART (highly active antiretroviral therapy) response, 194, 195, 231 Human papillomaviruses, 12, 160–164, 191 associated diseases, 161 cancer causation, 161, 163 DNA integration into host chromosomes, 161 E5 protein, 162 E6/E7 proteins, 161, 162–163 genetic determinants of susceptibility, 181 genome, 161 immune response, 163–164 vaccines, 246–247 Human T lymphocyte tropic virus type 1, 26, 143, 152 host cell transcription modulation, 44 trans-activating oncogenesis, 154–155 transmission, 24 Human T lymphocyte tropic virus type 2, 26 Hv-2 locus, 178 IgA, 16, 18, 78, 84, 245, 246 IgG, 78, 84 IgM, 78 Immortalization, 146–147 large DNA viruses accessory proteins, 158 Epstein-Barr virus, 166, 167, 168 human herpesvirus 8, 170 small DNA viruses, 158 human papillomaviruses, 163 SV40, 165 Immune complexes see Antigen–antibody complexes Immune response (acquired immune response), 39, 53, 72–85, 123 acute infection clearance, 132, 133 antibody production, 74–76, 78 cells, 72–74 cellular immunity, 75, 78–81 genetic analysis, 76 human immunodeficiency virus, 191–193 human papillomaviruses, 163–164 innate immune response relationship, 68–69 mucosal, 83–84 recovery from initial infection, 82 reinfection, 82–83 see also Innate immunity Immune surveillance evasion, 84–85, 131, 133–139 antigenic variation, 137–139 immunologically privileged sites, 136 impaired cytolytic T cell function, 137 intercellular bridges, 136–137 MHC Class I molecule expression down regulation, 46–47, 137 Immune-mediated viral disease, 88–89 antibody-mediated, 95–96 autoimmunity, 96–97 cell-mediated, 89–95 Immunologically privileged sites, 136 Immunosuppression, virus-induced, 99–109 age-related differences, 108–109 animal virus models, 104–106 human immunodeficiency virus, 76, 107–108, 197–198 human infections, 106–108 lymphocytic choriomeningitis virus, 100–101, 104–105, 108–109 measles, 99, 100, 106–107 mechanisms, 99, 100, 197–198 cytokine-mediated, 104, 127 immunomodulatory viral proteins, 103–104 innate immune response blockade, 104 lymphoreticular system cell infections, 99–102 tolerance, 102–103 virus strain differences, 108 Inactivated virus vaccines, 235, 238–239 efficacy, 238 safety, 238 Inbred mouse strains, 11, 12 Incubation period, 4, 115 rabies, 242, 243 Infancy rubella, immunosuppressive activity, 107 susceptibility to viral infection, 181–182 tolerance/persistent infection, 181, 182 Infectious mononucleosis, 166 Influenza virus, 18, 24, 60 antiviral therapy, 226, 227–228 M2 inhibitors, 227–228 neuraminidase inhibitors, 228 cold adapted variants, 117, 118, 235–236 vaccine strains, 119 entry pathway, 32 escape mutants, 228 hemagglutinin, 32, 33 1918 pandemic, 126, 210 RNA interference suppressor protein, 123 susceptibility, genetic determinants, 175 type A, 209–210 glycoprotein receptor (sialic acid) binding, 29–30 M2 protein ion channel function, 47 receptor destroying enzyme (neuraminidase), 30 vaccines, 238 263 Index virulence, genetic determinants, 126 Innate immunity, 10, 11, 39, 59–70, 72, 122–123 acquired immune response relationship, 68–69 cells, 61–63 viral protein perturbation, 104 Insect vectors, 16, 25, 96, 206, 207, 208, 213 Insertional mutagenesis, 148–149, 150, 153 Intercellular bridges, 136–137 Intercellular junction disruption, 50, 51 Interferon, 39, 60, 64–66 therapeutic applications, 227 hepatitis B, 229–230 hepatitis C, 229 type (α, β), 61, 63, 64–65, 66, 69, 100, 211 influenza virus susceptibility, 175 type γ, 62, 63, 65, 66, 73, 76, 80, 81, 89 viroceptor blocking activity, 104, 127 Interferon receptors poliovirus tropism, 34, 35 poxvirus homolog (BR8), 104 Interleukin (IL-2), 73, 76, 80 Interleukin (IL-4), 16, 73, 75, 76, 127 Interleukin (IL-5), 73, 75, 76 Interleukin (IL-6), 69 Interleukin (IL-8), 127 Interleukin 10 (IL-10), 106 Interleukin 12 (IL-12), 65, 69, 106 Interleukin 15 (IL-15), 65 Interleukin 17 (IL-17), 73, 76 Interleukin 21 (IL-21), 73, 75, 76 Intracellular cytokine staining, 79–80 Intracellular signaling, interferon activation, 65, 66 viral attachment response, 43 Ion channels, viral protein functions, 47 JAK-STAT pathway, 65, 66 Japanese encephalitis vaccine, 239 JC virus, 12, 135, 136, 143, 165 Junin virus, 207 Kaposi’s sarcoma, 12, 49, 107, 160, 168–170, 191, 217 human herpesvirus in etiology, 169 pathogenesis, 169–170 Kaposi’s sarcoma-associated herpesvirus see Human herpesvirus Kawasaki disease, 218 Kidney, persistent infections, 136 Kilham’s rat virus (hemorrhagic encephalopathy), 215 Killer inhibitory receptors (KIRs), 62 Knockouts, 9, 76 La Crosse virus, 114, 119, 203 effect of passage on virulence, 116–117 RNA interference suppressor protein, 123 virulence, genetic determinants, 124–125 Lactic dehydrogenase virus, 20, 137 Lamivudine, 230, 231 Latency-associated transcript, 122, 140 Latent infection, 50, 85, 130, 131, 135–136, 139, 143 activation, 136 cell-associated viremia, 20 Epstein-Barr virus, 167 herpes simplex virus, 122, 135, 136, 139–141 human herpesvirus 8, 170 human immunodeficiency virus, 190, 193–194, 196–197 varicella zoster virus, 23, 135, 136 virulent/attenuated virus comparison, 122 LD50, 115 Lentiviruses, 137, 185–186 immune response, 135 MHC Class I molecule expression downregulation, 137 vectors, 10 Limiting dilution assay, 78–79 Local immunity, 179–180 Local spread, 19 Long terminal repeats (LTR), 37, 38, 147, 148, 153, 154, 155 Lymph nodes, spread of infection, 19, 20 Lymphocyte surface markers, Lymphocytic choriomeningitis virus, 8, 9, 20, 21, 26, 80, 123, 136, 207 antigen–antibody (immune) complex-mediated renal disease, 95 antigenic variation, 138 cell-mediated immunopathology, 90–92 genetic determinants of susceptibility, 178 host growth hormone transcription modulation, 43–44 immunsuppressive actions, 100–101, 104–105, 108–109 persistent infection, 88–89, 131, 133, 134, 137, 178 receptor, 36 tolerogenic infections, 9, 102–103 M (microfold) cells, 18, 37, 189 M2 protein, 47 inhibitors, 227–228 Machupo virus, 207 Macrophages, 15, 17, 18, 64, 73, 74 Fc receptors, 73, 77 persistent infection, 137, 141 viral clearance, 20 viral infection human immunodeficiency virus, 101, 107, 186, 187 lymphocytic choriomeningitis virus, 100, 105, 109, 123 simian immunodeficiency virus, 189 Magainin, 223 Major histocompatibility complex (MHC), expression modulation following viral infection, 45–46 susceptibility determinants, 175, 178 HIV progression to AIDS, 180, 198 see also MHC Class I molecules; MHC Class II molecules Marburg virus, 215–126 Marek’s disease virus, 116, 127, 128 Mean transit time, 20 Measles, 4, 25, 27, 137, 143 age-specific susceptibility, 181, 183 human immunodeficiency virus interaction, 50 inactivated vaccine, 238 persistent smoldering infection (subacute sclerosing panencephalitis), 137, 142 re-emergent outbreaks, 206 virus-induced immunosuppression, 99, 100, 106–107 MHC Class I molecules, 53, 62, 63, 64, 65, 69, 73, 80 antigen presentation, 75 attenuated virus peptide loading, 236 CD8 T cell receptor interactions, 76, 89 downregulation following infection, 45, 46, 103–104, 137 MHC Class II molecules, 53, 69, 73 antigen presentation, 74, 75 attenuated virus peptide loading, 236 CD4 T cell receptor interactions, 74–75 Microtubules, 50 Milk, viral shedding, 24 Mitotic spindles, 50 Molecular biologic methods, 9–10, 216–218 Molecular mimicry, 97 Monkeypox, 211–212 Monoclonal antibody resistant variants, 118 Monocytes, 73 p15E protein immunosuppressive activity, 103 viral infection, 19, 20, 21 dengue, 96 human immunodeficiency virus, 101, 107, 108, 186, 187 measles, 99, 106 Morbilliviruses immunsuppressive actions, 105 persistent smoldering infection, 142 Mouse hepatitis virus, 30, 31, 32, 121, 178 Mouse mammary tumor virus, 24 Mouse polyomavirus, 164 264 Index Mousepox (ectromelia), Mucosal immune response, 83–84 rotavirus vaccine, 245, 246 Mucous membranes viral entry, 15–16, 17 viral shedding, 24 Multiple sclerosis, 12 Mumps, 21, 24 Murine AIDS virus (MAIDS), 105–106 Murine leukemia virus genetic determinants of susceptibility, 177–178, 179 immunosuppressive actions, 105–106 oncogenesis, 148–149, 152–154, 155 Mutagenesis, 118 attenuated virus characterization, 118–119 Mx protein, 175 Myelin basic protein, 97 Myxoma virus, 39, 115, 211, 213 Nasopharyngeal carcinoma, 166 Natural antibodies, 67 Natural killer (NK) cells, 53, 62–63, 64, 65, 69, 77, 89–90 Necrosis, 48–49 Nectins, 33 Nef gene/Nef protein, 45–46, 47, 186 Neural spread, 21–23 Neuraminidase, 30, 37, 209 inhibitors, 228 Neurotropic viruses, 6, 14, 21–23, 38 virulent/attenuated virus comparison, 119–120, 121, 122 Neutralization index, 76 New viral agents see Emerging diseases Newborn infants hepatitis B infection, 182, 244 retrovirus infection, 147 susceptibility to viral infection, 181 tolerance induction, 102, 182 Newcastle disease virus, 37 Nuclear pore complex, 33 Oas1b, 177 Old age, susceptibility to infection, 183 Oncogenes, 7, 9, 10, 154, 158 acute transforming retroviruses, 149, 151 Oncogenesis, 27, 146–147 DNA viruses see DNA tumor viruses multistep process, 160, 166, 167 retroviruses see Retroviruses Opsonization, 77 Oral fluids, viral shedding, 24 Oral poliovirus vaccine, 9, 115, 205, 236, 241, 242 genetic determinants of attenuation, 125–126 interference, 237 reversion to virulence, 125, 205, 237 Oropharynx viral entry, 17–18 viral shedding, 24 Oseltamivir, 228 p15E, 103 p53 gene/p53 protein, 158, 159, 160, 162, 163, 164, 166, 167, 170 Papillomas see Warts Papillomaviruses, 15, 17, 24, 49 oncogenesis, 158, 160–164 replication/skin tropism, 37, 38 Paramyxoviruses, 37 Parvovirus B19, 24 erythrocyte precursor tropism, 35 receptor, 35–36 Parvoviruses, 49 age-specific susceptibility, 182–183 Passage, virulence manipulation, 116–117 Pathogen-associated molecular patterns, 60, 63, 69 Pattern recognition receptors, 60, 63 Perforin, 80, 89, 91, 137 Persistent infection, 25–26, 88, 130–144 antigen–antibody complex formation, 95 antigenic variation, 137–139 antiviral therapy, 226 associated diseases, 143, 144 cell culture models, 131–132 duration, 133 foot-and-mouth disease, 211 hepatitis B, 26, 88, 131, 133, 134, 142–143, 182, 244 high titer with immune tolerance, 133–135, 139, 143 lytic viruses, 135 non-lytic viruses, 133–134 retroviruses, 147 human immunodeficiency virus, 26, 32, 133, 194, 196, 231, 248 immunologically privileged sites, 136 impaired cytolytic T cell function, 137 infectious immune complexes, 137 latency see Latent infection lymphocytic choriomeningitis virus, 88–89, 131, 133, 134, 137, 178 mechanisms, 130–131, 133–139 MHC Class I molecule expression downregulation, 137 newborn infants, 181, 182 smoldering infections, 131, 136–139, 143 Theiler’s murine encephalomyelitis, 93, 141–142 Picornaviruses, persistent infection, 141–142 Plaque assay, 8, 76 pol, 147, 151, 185, 249 Poliovirus, 3, 6–7, 8, 12–13, 20, 24, 27, 174, 183 age-specific susceptibility, 182 antibody, 7, 240–241, 242 acute infection clearance, 132 apoptosis induction, 49 attenuation, reversion to virulence, cell culture, 214, 215 effect of passage on phenotype, 117 emergence of epidemic disease, 204–205 host cell alterations, 43, 44 receptor, 34–35 shedding, 24 spread of infection, 15, 18 tropisms, 22, 23, 38–39 type eradication, 26 vaccine, mechanism of protection, 240–242 oral see Oral poliovirus vaccine vaccine-derived, 205 viremia, 119 virulence determinants, 119, 121 genetic, 125–126 virulence measures, 115 Polyomaviruses, oncogenesis, 158, 164–165 Post-transplant lymphoproliferative disease, 166 Poxviruses, 15, 18, 39 exit from host cells, 50 immunosuppressive activity, 103, 104 oncogenesis, 158 virulence determinants, genes of cellular origin, 127 Pregnancy, 183 Progressive multifocal leukoencephalopathy, 12, 135, 165 Promoter insertion, 148 Protein synthesis, host cell, 44, 45 Proto-oncogenes, 149, 154 activation by insertional mutagenesis, 153 Pseudorabies, 23 Pulmonary adenomatosis (jaagsiekte) of sheep, 152 Quantitative studies, historical aspects, Rabbit hemorrhagic disease virus, 213 Rabies, 3, 8, 24, 133, 207 incubation period, 242, 243 neural spread, 16, 22 vaccine, 239 attenuated strain, 119–120 mechanism of protection, 242–243 post-exposure prophylaxis, 242–243 pre-exposure prophylaxis, 242 virulence, 116 Receptors, host cell, 27 alterations following infection, 45 cognate, 30–31, 32 genetic determinants of susceptibility, 178 glycoproteins, 29–30 non-protein, 30, 31 tropism determination, 34 265 Index viral attachment, 28–32 viral entry, 32–33 Recombinant protein vaccines, 235, 238–239 Recombinant virus vaccines, 239 Reinfection (superinfection) antibody response, 82–83, 84 human immunodeficiency virus, 248–249 immune response, 192–193 resistance, 45 Reoviruses, 22, 24 apoptosis induction, 43, 48 gastrointestinal tract entry, 18, 37 persistent infection in cell culture, 132 virulence/attenuation, 116, 121 genetic determinants, 123–124 Replication, 10–11, 37, 38 cytopathology relationship, 42 genetic determinants of susceptibility, 175, 177–178 host cell effects, 42 cell cycle, 49–50 retroviruses, 147, 187 temperature sensitivity, 37 Replicons, 239 Respiratory syncytial virus, 92–93, 238 Respiratory tract viral entry, 18, 19 viral shedding, 24 Retinoblastoma protein (Rb/pRb), 158, 159–160, 162, 164, 167, 170 Retroviruses, 7, 9–10, 146–156, 185–186 gene therapy vectors, 149, 156 high titer persistent infection with tolerance, 147 oncogenesis, 148–152 acute transformation, 149, 151–152 avian sarcoma and leukosis viruses, 154 cellular specificity of induced tumors, 155 human T lymphocyte tropic virus type 1, 154–155 insertional mutagenesis, 148–149, 150, 153 multifactorial induction process, 155–156 murine leukemia viruses, 152–154 non-acute transformation, 148–149 trans-activation by accessory genes, 152, 154–155 viral proteins, 152 provirus integration into genome, 147, 149 susceptibility determinants, 175, 178 replication, 147 helper virus requirement, 147, 151, 152, 154 structure, 147 Reverse transcriptase, 7, 147, 185 inhibitors, 230, 231 Rhinoviruses, 18, 24, 27, 32, 37 Ribavirin, 222, 229 Rimantadine, 228 Rinderpest virus, 105 RNA interference, 10, 53, 68, 76 therapeutic applications, 222–223 viral suppressor proteins, 122–123 Rotaviruses, 24, 215 vaccine, mechanisms of protection, 245–246 Rous sarcoma virus, 6, 7, host cell transformation, 10, 154 Rubella, 137 congenital syndrome, 107 fetal/infantile infection immunosuppressive activity, 107 tolerance, 182 Saliva, viral shedding, 24 Selection attenuated virus variants, 117–119 cold adapted viruses, 117, 118 monoclonal antibody resistance, 118 mutagenized viruses, 118–119 passage in carrier cultures, 132 temperature sensitive mutants, 117, 118 Sendai virus, 42 Severe acute respiratory syndrome (SARS) virus, 116, 121, 208–209, 211, 214 angiotensin converting enzyme receptor, 121 Sexual transmission, 17, 25, 183, 189 Shedding, 4, 14, 23–24, 26 Sialic acid residues, 29–30, 32, 37 Simian human immunodeficiency virus (SHIV), 247 strain differences in immunosuppression, 108, 123 tropism determinants, 39, 196 Simian immunodeficiency virus, 143, 185, 186, 188 antibody response, 192 escape mutants, 138 non-pathogenic infections, 196–197, 198 persistent infection, 135 progression to AIDS, 180, 196 species barrier passage/human immunodeficiency virus emergence, 210 transmission, 189 vaccine development, 247, 248 Simian virus 40 (SV40), 214–215 entry pathway, 33, 34 oncogenesis, 164–165 Sin Nombre virus, 204, 214, 217 Sindbis virus, 23, 49, 80, 182 Skin papillomavirus replication, 37, 38 viral entry, 15–17 viral shedding, 24 Smallpox (variola), 6, 10, 11, 24, 26, 27, 116, 174, 234 age-specific susceptibility, 182 Smoldering infections, 131, 136–139, 143 Theiler’s murine encephalomyelitis virus, 141–142 Species barrier, 208, 211 Spontaneous generation, 4–5 Spread, 14, 19–23 blood to tissues, 21 local, 19 neural, 21–23 viremia, 19–21 src oncogene, 10, 154 Steps in viral infection, 14–26 Subacute sclerosing panencephalitis, 137, 142 Superinfection see Reinfection Susceptibility, 174–183 age-specific, 181–183 emergence of epidemic disease, 204–205, 206 gender-specific, 183 genetic determinants, 11, 174 human diseases, 179–181, 198 immunological, 178–179 loci, 176 mouse models, 175–179 non-immunological, 175–178 re-emergence of infections, 205–206 Syncytium formation, 42, 187, 188 T cell receptor, 53, 73, 74, 80 MHC Class I molecule interactions, 76, 89 MHC Class II molecule interactions, 74–75 T cells, 65, 72 measles-related decrease, 106, 107 memory cells, 81, 82, 234 tolerance-related alterations, 134 p15E protein immunosuppressive activity, 103 viral infection, 19, 20, 21, 99 see also CD4 T cells; CD8 T cells Target organ invasion, virulent/attenuated virus comparison, 120–121 Tax gene/Tax protein, 44, 152, 154, 155 Telomerase, 162, 167 Temperature sensitive strains, 18, 37, 117, 118 Tenofovir, 230 Tetramer assay, 79 TH1 cells, 73, 76 TH2 cells, 73, 76 activation, 74–75 Theiler’s murine encephalomyelitis virus, 90, 143 cell-mediated immunopathology, 93 persistent smoldering infection, 141–142 Tick-bone encephalitis vaccine, 239 Tobacco mosaic virus, 266 Index Tolerance, 9, 20, 85, 99, 102–103, 131 mechanisms, 134 newborn infection, 181, 182 persistent high titer infections, 133–135, 142–143 Toll-like receptors, 21, 60–61, 63–64, 127, 240 Transcription, host cell response, 43–44 Transformation, 146–147 large DNA virus accessory proteins, 158 small DNA viruses, 158 adenovirus, 165 human papillomaviruses, 163 SV40, 164, 165 Transgenes, 9, 76 tissue-specific promotors, 10 Transmission, 24–25, 26, 214 acute infections, 25 chronic infections, 25–26 efficiency, 25 historical aspects, 3, vertical, 26 Transportation, spread of new infections, 211 TRIM5α, 51, 188 Tropism, 14, 27, 34–39 attenuated vaccine viruses, 235, 236 determinants, 36 anatomical barriers, 38–39 cellular proteases, 36–37 cellular receptors, 34–36 cellular transcription factors, 37, 38 enteric viruses, 37 host immune response, 39 pH lability, 37 replication temperature, 37 viral variation, 39 virulent/attenuated virus comparison, 121–122 Tumor necrosis factorα, 21, 62, 69, 80, 81, 89, 106 Tumor necrosis factor viroceptors, 127 Tumor suppressor genes, 159 Undernutrition, 183 Urban populations, spread of new infections, 211 Urine, virus shedding, 24 Urogenital tract, virus entry, 17 Vaccines, 26, 234–251 attenuated viruses, 235–238 DNA-based immunogens, 239–240 established products, 236 mechanisms of protection, 240–247 immune induction principles, 235 inactivated viruses, 235, 238–239 recombinant proteins, 235, 238–239 recombinant viruses, 239 replicons, 239 subunit, 235, 238–239 vectors, 239–240 Vaccinia virus, 6, 127, 234 complement cascade blockade, 103, 127 complement control protein, 127 recombinant vaccine production, 239 RNA interference suppressor protein, 123 Valacyclovir, 232 Varicella zoster virus, 143, 191 antiviral therapy, 232 latent infection, 23, 135 activation, 136, 183 persistent infection, 26 spread of infection, 22, 23, 24 Variola see Smallpox Vertical transmission, 26 human immunodeficiency virus, 189 Viral attachment proteins, 28, 29, 32 receptor binding, 29, 30 receptor-binding domain, 32 Viral polymerase inhibitors, 231–232 Viremia, 19–21 cell-associated, 20–21 mean transit time, 20 passive, 19 plasma, 20 primary, 20 secondary, 20 virulent/attenuated virus comparison, 119 Viroceptors, 104, 127 Virokines, 127 Virulence, 113–128 comparative pathogenicity studies, 119–123 emerging disease outbreaks, 205 experimental manipulation, 116–119 genetic determinants, 123–126, 127 genes of cellular origin, 127 host intrinsic response, 122–123 measurement, 114–116 Visna/maedi virus, 21, 24, 137, 143 Warts, 24, 161, 163, 164 Water-borne transmission, 25 West Nile virus, 21, 22, 82, 83, 133, 206, 214 susceptibility age-specific, 183 genetic determinants, 177, 179 therapeutic antibody, 227 vaccine, 239 virulent/attenuated virus comparison, 122 Western blot, 76, 77, 191–192 Western equine encephalitis, 182 Wnt signaling pathway, 170 Xenotransplantation, 214 Yellow fever, 3, 5, 6, 27, 116, 206, 207, 212, 214 vaccine, 237–238, 239 Zanamivir, 228 Zoonotic infections, 206–211 deadend hosts, 207–208 human-to-human limited transmission, 208 species barrier passage, 208–211 ... Interactions Viral Virulence Neal Nathanson and Francisco Gonzalez-Scarano 10 Viral Persistence Neal Nathanson and Francisco Gonzalez-Scarano 130 11 Viral Oncogenesis: Retroviruses Neal Nathanson and. .. Virus–Cell Interactions Neal Nathanson and Diane E Griffin 41 Part II Host Responses to Viral Infection 57 Innate Immunity Neal Nathanson and Christine A Biron 59 Immune Responses to Viral Infection Neal.. .Viral Pathogenesis and Immunity This page intentionally left blank Viral Pathogenesis and Immunity Second edition Neal Nathanson Departments of Microbiology and Neurology University of Pennsylvania