Medical Virology

Citation preview

David 0. White Department of Microbiology University of Melbourne Parkville, Victoria, Australia

Frank J. Fenner The John Curtin School of Medical Research The Australian National University Canberra, ACT, Australia

7FfE IfbllWERSCfY OF NEW MEXICO HEALTH SCIENCES CENTER U€WtiW ALBUQUERQUE, NEW MEXICO37331-15686

Academic Press SanDIego

NewYork

Boston

London

Sydney

Tokyo

Toronto

Coverphoto: Computer graphic representation of the virion of human rhlnov~rus14 along the icosahedral 3-fold axis of symmeq, highlighting the topographic deta~llsof the surface. Lighter colored structures are situated further away from the virion center, showing that the icosahedral5-fold axis region is the most prominent feature. The "canyon" is clearly seen as a dark blue depress~onaround the 5-told axis and is the binding slte for the cel'lular receptor ICAM-1. A depressron is visible at the icosahedral:Zfold axis of symmetry (equidistant between two 5-fold vertices), but has no known role. Antibody binding sites detemrned by escape mutations are shown in magenta and clearly appear in more exposed (white or light blue) areas on "domes" and "ridges." suggesting that the dark Blue areas are not within the reach of antibodies. (Courtesy of Dr. Jean-Yves Sgro.)

Contents

This book is printed on acid-free paper.

Preface

xv

Copyright O 1994, 1986,1976,1970 by ACADEMIC PRESS, INC. All R~ghtsReserved No part of this pubhcation may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, record~ng,or any information storage and rettieval system, without perrnasslon in writing from the publrsher.

Part I

Principles of Animal Virology Chapter 1 Structure and Composition of Viruses

Academic Press, Inc. A Division of Harcourt Brace & Company 525 B Street, Suite 1900, San Diego, California 92 101-4495 United Ongdnm Edrrion puhli~hedby

Academic Press Limited

Viral Morphology 4 ChemicaI Composition of Virions 10 14 Preservation of Viral Infectivity Further Reading 15

24-28 Oval Road. London NW I 7DX

Library of Congress Cataloging-in-Publication Data White, David 0. Medical virology I by David 0.White, Frank J. Fcnner. p. cm. Order of authors reversed on previous eds Includes index. ISBN 0- 12-746642-8 I Medical virology I. Fenner, Frank, DATE. 11. T~tle. QR360.F43 1994 61 6' 01 94--dc20 93-48068 CIP PRINTED FN THE 'UNITED STATES OF AMERICA 9 4 9 5 9 6 9 7 9 8 9 9 MM 9 8 7 6 5 4 3 2 1

Chapter 2 Classification and Nomenclature of Viruses Criteria for Viral Classification 16 Nomenclature 17 Families of DNA Viruses 17 Families of RNA Viruses 22 Other Viruses 27 Groupings Based on EpidemiologiciPathogenic Criteria Further Reading 29

Chapter 3 Viral Replication The Viral Replication Cycle 31 Attachment 33 Uptake (Penetration) 35 Uncoating 36 Strategies of Replication 36 Transcription 41

28

',

Contents

Transla tion 45 Replicatic~nof Viral Nucleic Acid Assembly and Release 49 Furtl-rer Reading 52

vii

Contents

48

Passive lmmunity Further Reading

Chapter 9

Chapter 4 Viral Genetics and Evolution Mutation 54 Genetic Recombination between Viruses

59 61

Interactions between Viral Gene Products Mapping Viral Genomes 62 Recombinant DNA Technology 64 Evolution of Viruses 66 Further Reading 72

76

92

Chapter 7 Determinants of Viral Virulence anld Host Resistance Viral Virulcsnce and Host Resistance 104 Genetic Determinants of Viral Virulence 105 Genetic Determinants of I-Eost Resistance 111 Physiologic Factors Affecting Resistance 114 Further Reading 118

Chapter 8 Immune Response to Viral Infections Compnncnts of the Immune System immune Responses to Viral Infection Rect-~veryfrorli Viral Infection 131

136 Viral Damage to Tissues and Organs Immunopathology 140 lrnrnuncrsuppression 144 Viral Infections in Immunocompromised Patients 146 Further Reading

145

Categories ol Persistent Infections 148 Acute Infections with Rare Late Coinplications Latent Infections 150 Chronic Infections 156 158 Slow Infections Pathogenesis of Persistent Infections 164 Further Reading 169

149

Chapter 11 Mechanisms of Viral Oncogenesis

Chapter 6 Mechanisms of Infection and Spread of Viruses through the Body Routes of Entry 87 Mechan~smsof Spread in the Body Virus Shedding 100 Further Reading 102

Mechanisms of Disease Production

Chapter 10 Persistent Infections

Chapter 5 Virus-Induced Changes in Cells TypesofVirus-CellInteractions 74 Cytnpathic Effects of Virus Infections Mechanisms of Cell Damage 80 Noncytocidal Infections 81 Interferons 82 Further Reading 86

134 135

120 129

Oncogenes and Tumor Suppressor Genes Cell Transformation 172 Tumor Induction by Retroviruses 174 Human T-cell Leukemia Viruses 181 182 Tumor Induction by DNA Viruses Papillomaviruses 1134 Hepadnaviruses 184 I-ierpesviruses 186 MuEtislttp Oncogenesis 188 189 Further Rcading

171

Chapter 12 Laboratory Diagnosis of Viral Diseases 191 Rational Use of the Laboratory 193 Collection, Packaging, and Transport of Specimens Direct Fdentificafion of Virus, Viral Antigen, or Viral Genome Virus Isolation 205 Measurement of Serum Antibodies 210 Laboratory Safety 236 Further Reading 217

195

viii

Contents

Contents

Part II

Chapter 13 Jmmunization against Viral Diseases I,ivu-Virus Vaccines 219 Inactivated Vlrus and Virus Subunit Vaccines 223 Synthetic Vaccines 225 DNA Vaccines 226 Anti-ldiotypic Antibodies 226 Methods for Enhancing Immunogenicity 226 Comparison of Different Classes of Vaccines 227 Further Reading 231

Chapter 14 Epidemiology of Vinl Infections Cornps~tationsand Data Used by Epidemiologists 233 238 Types of Epidemiologic Inves tiga tions Virus Transmission 242 Mechanisms of Survival of Viruses in Nature 244 Further Reading 255

Chapter 15 Prevention, Control, and Eradication of Viral Diseases Quarantine 256 Hygiene and Sanitation 257 Vector Ccmtrol 258 Change of Lifestyle 259 Immunization 259 2153 Eradication Further Reading 265

Chapter 17 Pflrvloviridac Propertics rrf Pnroovirirl'Re 285 Parvovirus 1319 288 Enterjc Parvavisuses 292 Dependoviruses 292 Fulther Reading 293

Chapter 18 Papovavirfdae Properties of Papcrvaviuidne Papillomaviruses 294 Polyomaviruses 302 Further Reading 304

Chapter 19 Adenoz)iridar! Properties of Adatoviridn~ Pathogenesis and Immunity (ClinicalSyndromes 310 Laboratory Diagnosis 312 Epidemiology 314 Control 314 Further Reading 315

294

306 309

Chapter 20 Nerpesoiridae

Chapter 16 Chemotherapy of Viral Diseases Strategy for Development of Antiviral Agents Clinical Apy lication 269 Interferons 271 Inhibitors of Viral DNA Polymerase 272 lnhibitrlrs of Reverse Transcriptase 276 Ic~nChannel Blockers 277 Bjocking Aftachment or Uncoating of Virion lnhihitnrs of Viral Proteases 279 Virus-Specific Oligonucleotides 279 Inhibitors of Regulatory Proteins 280 Further Reading 2X(1

Viruses of Humans

267

Properties lol Ncrpesnirid~e 318 Herpes Simplex Viruses 323 VariceJla-Zoster Virus 330 Cytornegalovirus 334 341 Human Herpesvirus 6 Epstein-Barr Virus 343 Werp~s'5 Virus 346 Further Reading 346

Chapter 21 Poxviw'dne 278

Properties of Pt~~tiiridnc 348 Pathogenesis and Immunity 352 La bnratory Diagnosis 352 Human Tnfe8ctionswith Orthopoxviruses 3ti3 Human infections wifh Parapoxvirwscs 356

I

!

Contents

Molluscum Contagiosuln 356 YabapoxandTanapox 357 Further Reading 357

Laboratory Diagnosis 437 Epidemiology and Control 438 YeZieIlow Fever 438 Dengue 441 Flavivirus Enrephali tides 443 Tick-Borne Flavivirus Hemorrhagic Fevers HepatitisC 445 Further Reading 449

Chapter 22 Hepadnaviridae and Deltauirus Properties sf Heyudnnairidne 359 Clinical Features of Hepatitis B 362 Pathogenesis and Immunity 364 Laboratory Diagnosis 366 Epidemiology 369 Control 369 Delfnvirus (Hepatitis D) 373 Further Reading 379

Chapter 27 Coronaviridae Properties of Coronaviridge 451 Pathogenesis and Immunity 454 Clinical Features 454 Laboratory Diagnosis 454 Epidemiology 455 Further Reading 455

Chapler 23 Picornaviridae Properties of Picornaviridae Polioviruses 385 0 ther Enteroviruses 391 Rhinoviruses 398 Hepatitis A 400 Further Reading 405

382

Chapter 28 firamyxoviridae

Chapter 24 Caliciviridae and Astroviridlae Caliciviruses Associated with Gastroenteritis Hepatitis E 411 Astroviruses 415 Further Reading 417

Chapter 25 Togaviridae Prnperties of Tognviridae 418 Pathogenesis 421 Clinical Syndromes 42'1 Laboratory Diagnosis 423 Epidemiology 424 Control 426 Rubella 427 Further Reading 432

407

Properties of Pararnyxovjridae 456 Measles 461 Mumps 465 Parainfluenza Viruses 467 Respiratory Syncytial Virus 469 Further Reading 474

Chapter 29 Rhabdoviridae Properties of Rh~~bdoviridue 475 Rabies 478 Vesicular Stomatitis 482 Further Reading 482

Chapter 30 FiCoviidae

Chapter 26 Flaviviridae Properties of Flniliviridn~ 434 Pathogl~nesisand Clinical Features

Contents

436

Properties of Silozliridae 485 Fa thogenesis 486 Clinical Features 486 Laboratory Diagnosis 487 Epidemiology 487 Prevention 487 Further Reading 488

445

xii

Con tents

Contents

Chapter 31 Orfkomyxovirfdae Properties of Or~lro~n:yxo7liurdrrexidue Pathogenesis and Immunity Clinical Features of Influenza LaboratoryDfagnosis 494 Epidemiology 495 Control 496 Further Reading 499

Human Sprtmaviruses 562 Further Reading 561

489 493 494

Chapter 36 Viral 'Syndromes Viral Diseases of the Respiratory Tract 564 Viral Gastroenteritis 569 Viral Diseases of the Central Nervous Sysfem 571 Viral Skin Rashes 576 Viral Hemorrhagic Fevers 579 Viral Genitourinary Infections 580 Viral Diseases of the Eye 581 Viral Arthritis 583 Viral Carditis 583 Viral Hepatitis 584 Viral Pancreatitis and Diabetes 586 Chronic Fatigue Syndrome 586 Congenital and Perinatal Viral Infections 586 Viral Infections in Imrnunocompromised Patients 588 Further Reading 589

Chapter 32 Arenaviridae Properties of Are~iaviridae 500 Laboratory Diagnosis 503 Epidemiology 504 Diseases Caused by Arenaviruses Prevention and Treatment 507 Further Reading 508

504

Chapter 33 Btrnyaviridae Prnperties of Butfya~iridue 509 Pathogenesis 513 Laboratory Diagnosis 513 Rift Valley Fever 513 Sandfly Fever 515 515 California Enoephalitis Qropouche Fever 516 Crimean-Congo Hemorrhagic Fever 517 Hemorrhagic Fever with Renal Syndrome 518 Furher Reading 5280

Index

Chapter 34 Reovitidae Properties of Rmviridae

522 Rotaviruses 524 Coltiviruses and Orbiviruses 528 Orthoreoviruses 529 Ft~rtherReading 530

Chapter 35 Rcfroviridae Properties of Retroz~iridae 532 Human T-cell Leukemia (Lymphotrupic) Viruses Human Immunodeficiency Viruses 538

535

591

Preface The aim nf this text is in present the fundamental principles of med ogy to students of science and medicine. It is also hoped that it will : useful resource for teachers of virology, specialists in infectious dise postgraduate students. The pace of change in the eight years since t ous edition has been so great that the book has necessarily been sub rewritten and expanded. The essential plan of previous editions retained, but our account of the molecrrlar biology of viral infection detailed than in Ihe third edition. Part I of the book presents an ovt the principles of animal virology, while Part 11, entitled Yiruscs of Hir, arranged by virus family, is oriented toward the needs of medical and clinicians. In order Oo focus on conccpts, mechanisms, and ba minutiae have been omitted except where necessary to understand a rant phenomenon. Much of the factual material is consolidated into t; figures. Statements have not been individually supported by refer research papers, but selective lists of recent authoritative books and are provided at the end of each chapter to simplify the reader's entry scientific Iitera twre.

Acknowledgments The indirect but invaluable input of our coauthors of Vderinrrry Vlrolc E. P. J. Eibbs, F. A. Murphy, R. Rott, and M J. Studdert, to this fnurtl of Medical Virolog.y is gratefully acknowledged. One of us (D.W.) is par grateful to Drs. F. A. Murphy and 8.W. J. Mahy for their hospitality three-month visit to the Centers for Disease Control and Prevention, Georgia, during the early stages of the preparation of this book. discussions with the fnllowing scientists in America or Australia are a edged: Drs. G. L. Ada, M. J. Alter, D. A. Anderson, L. J. Anderso~ Baer, M,J. Beach, W. J. Bellini, R. V. Blanden, D. W. Bradley, C. H. ( N. J. Cox, L. Dalgarno, 12. Doherty, D. and M. J. Dyal S. P. Fisher-Hoch, H. A. Fields, T. M. Folks, J. R. L. Forsyth, K . Hay( F-ferrmann, J. C. Hierholzer, I. H. Holmes, A. P. Kendal, 0. M. Kc, Locarnini, B. W. J. Mahy, H. S. Margolis, I. D , Marshall, 1: P. 1 S. S. Monroe, E. A. Murphy, M. A. Pallansch, P. E. Pellett, 1-i. G. Pere Peters, M. A. Purdy, W. C . Reeves, A. Simmons, and E. G. and J. H. We are also indeblted to those scientists and publishers, too numc mention here, who responded generously to our requests for illustra lerial; appropriate acknowledgments accompany the Iegends to figu are particularly grateful to Dr. Jean-Yves Sgro, who provided the Icolor image of a rhinovirus particle that decorates the cover. We are gr, Mr. Kevin Cowan for once again helping with the preparation of lit1 ings a n d to the Photographic Section of the John C t ~ r t School i ~ ~ of Ixesearch for preparing the illusfrations for yublica tion. Last but not I( White would like to record I-aisappreciation of the forbearance of his r colleagues Drs. E. M. Anders, L. E. Brown, and D. C. Jackson, anc graduate students in the llabora tory during the three-year gestation p this book and to thank Nadia PuglielIi and Belinda L.ightfoot for the! verance and devotion in the preparation of the manuscript. Light and Michael Early of Academic Press have been most con1 throughout the production nf this edition.

xvii

P a r tI

Principles of Animal Virology

c h a p t e r1

Structure and Composition of Viruses -

Viral Morphology. .... . 4 Chemical Composition of Virions. .....10 Preservation of ViraP Infectivity..... . I 4 Further Reading. ..... I 5 -..

The unicellular microorganisms can he arranged in clrcfer of decreas~ngslztL and complexr ty: protozoa, fungi, and bacteria- the latter including mycopfasmas, rickettsiae, and chlamydiae, whlch, like viruses, replicate within eukaryotic ,cells. These microorganisms, however small and simple, are cells They always contain DNA a s the repository nf genetic information, they also contain RNA, a n d they have their own machinery for producing energy and macrc~moIeruIes.Unicellular microorganisms grow by synthesizrng their own macrlcrmnlecular constituents (ntlcleic acid, protein, carbohydrate, and lipid), and most multiply by binary fission Viruses, on tht olhtr hand, are riot cells. They possess ncs functional organelles a n d are completely dependent on their cellular hosls For the machinery of energy production and syntl~esisof macromnlecules. Thcy conta~rl only one type of n ~ ~ c l eacid, i c either DNA or RNA, but ncver both, and thcy differ from nonviral organisms in having two clearly defined phases in thcir lafe cyclc. Oulside a srrscvptible cell, the virus parficle is metabolicaljy Inert, i f is the transmission phase of the virus. This extracellular transmission phasc altcrnates wit11 a n intracellular reproductive phase, in which the viral genomrq exploits the nietabolic pathways of the hnst t c produce ~ progeny gennmes ancl vlral proteins that assemble to form new virions. Furlhcr, itnlike a n y uniccllujar microorganism, many viruses can reproduce Lhemselves even if noiliing but the viral g e n c m c is introduced into thcl cell The key differences between viruses and unicellular microorganisms arty lislcd in Table 1-1. Several imprlrtant practical conseililcnccs flow from thrlsra differences. Fur example, some viruses can persist 111 cells by tlie integration ol their DNA (or a DNA copy oC thcir RNA) into tho genvmr of thc host cell

4

Viral Morphology

Chapter B Structure and Composition of Viruses Table 1-1 C ( i r i t r c i \ ! ~ t i c~'rop(,rt~c,q(I( U r i i ~ . c l I ~M1~r(iorg~i111511>% ~l~~ < I I ~ L ~illr~tif.-\ --

I'rt?pt*rty :-1011 n m t l ~ ~ ~ r n c t e r " G r l ~ w t F on l nrlnllvlng mcdla" liiriary f ~ % v c ? n UNA .and R N A N ~ i c l r l c, ~ r ~~ nd l t n c t l c c ~ ~ ~ \ R~Po.;r>mcs Mrt,ihcrl~.;n~ S v n s ~ l t ~ v lo ~ t ya i i l ~ h i o l ~ c s

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c*leclrnl.arnlcroscrlpy of viruses A solulic>n of ~ ~ o t , ~ s s ipi ~ l i rr~ns p l i r ~ L u ~ ~ ) = s L ~ ~ t e , W ~ I C is ~ Ian electron-dense sall, w h e n used to .;tan virus particles, fills thc interstices of the viral surface, ~ ~ V I I I Fl ;l ~ ercsult~ngclcctron microgmpli a degree of dcta~lnot prcvionrsly possible (Fig 1-1) IZlcctron rnicrc~gr~~phs of negatively staancd preparations crf virions reprec;enhtig flit families of viruses that cat~seRuman infcctinns are shown in thc chapters of Part IF of this book.

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I3actvr1~1 h l v r e ~ l ~ l ~ i r nK~rkcfil\lac ~l~ C t l l a ~ n v d ~ a c Vlrcr5ci ~

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Strnlc. niycopla5rnas and c h l a n ~ y d ~ , l mcasurc t. arouncl 3(3(1[iln o r less Chlarnycli~iea n d mcr5t r~ckcxtt.;~arare obl~g;itr ~ n t r a c c l l u l a rp a r i w ~ l c s S o i i ~ t .among h r t h I I N A a n d R N A i r l r u s c s CV~tlii.t.ry uxccpf~i~n\ f 1 . 3 ~

Viral Structure Tlne uirlon (infectious virus particle) of tlie simplc->stvlruses consisls of a single molecule of nucleic acid surrounded by a protein coat, the nzp..;rd,the capsid and associated nrlcleic acid constrtute the ~rrrrIt~orn~?srrf. 'I'hc nucleocapsid of some viruses is surrounded by a lipoprotein ( I ; I ~ s . I - I B and 1-2C,D). In some of the more complex viruses the capsid surrtmnds a pmlein core, which encloses the viral rii~clcicacid. Thc capsid is composed of a defined number of morphological units

Mnrcovcr, viruses are not susceptible to antibiotics that act against specific steps In thc rnetabtdic pathways of bacteria. The simplest conventional viruses consist of a nucleic acid genome and a protein coat. However, there exists a clcissof even simpler infectious entities ktinwn as olrclids, which are infectious RNA molecules that lack a protein coat; as viroids have so far been fcrund only in plants thcy are not discussed further in thrs book. En contrast, Ilrrotrs, such as the agents that cause the spongiform enccphalopathies in humans, appear lo be a filamentous protein with no assoc~nlrdl~iucleicacid.

Viral Morphology

I

Physical Methods for Studying Viral Structure 11 has becn k n o w n for many years that viruses are smaller that1 microorganisms. I'he first unequivocal dernonstsatir-rn of this for an anirual virus occurrrd in 1898, when Luefller and Frosch demonstrated that foot-andrnr~rltlidisease, an impurtant- infectious disease of cattle, could be transferred by mntcr~alwhich could pass through a filter of average pore diameter tun small to allnw passage of bacteria The new group of "nrganisms" became knrrrun as t h r "filterable ~riruses" For a time thpy were alsn called "ullrariiicroscnp~c,"since c most viruses are beyclnd the Binlit of resolution of Iight r~~icrt).;copes[200 nanometers (nm) = 2000 angstroms (A)]. Only with the acilvcn t of the electron ~nicroscopewas it possible to study the morphology nf vlrulsrs properly I 1 then became apparent that they range in s i ~ efrom about the. S ~ P Cof f l ~ esmallest rn~cmclrganismsdown to little bigger than the largest prntcul n~olcculcs. Early elecY ron m~lcrosct~pic studies o l viruses by Ruska in 1939-1941 were cxpnnrlcd d u n ~ . ~lhc y : 1950s tt.r include thln stctioning of intected cells and mrtal s h a d o w ~ n gof purif~edvirus particles. Then in 1959 our knowlec-lgk of viral l i l t rClstruct~~rc was transforlned whr*ntrr~,~mfrzril slnirrirrlt) was applied Lo L l ~ t

Fig. 1-1

M o r p l i n l n g ~ r a lfCatrlre.; n l viral strncturc revc7afcd bv r i c g a t ~ v cs t a ~ n ~ nagn d ellcctron niacro5cnFv (bars. 1Ot)nm) (A) V ~ r o r j ncrl a n aclrnovirrns, \ l l r w . . ~ n ~ccrsnhrclral ~ capslcf cr!mycrst>d r ? l liexrans, prrilnns, and llht:~s p ~ o j c c t i n gf r o m v r r l ~ c c s( c o i n ~ l a r ew l t l ~FIR I-2A). (R) t : n v c l o y t ~ d vlrutlt~of ~ n l l ~ ~ c ~vnrlls n x a Thr Iwo type\ crf peplorn~rs,h r * n ~ , l g x l t l l ~ na~nnd n c ~ r r a m ~ n ~ d aarc sc, visible but ntlt c i ~ s t ~ n g u i s l i a h lItn. ih15 electron cnicri!grapli [c~rrnp;lrc, WJI~II FIR 1-21]), n o r art3 t h r liiel~cialn ~ ~ c l r n c a y s ~ du. s; u a l l y v ~ s ~ h(hut l r s c r Fig 31-1) (C') N ~ ~ r l c o c ~ irrf l ~p,lrci~rirlutsn/a s~d virus ' r h r RNA 15 w o u n d ~ v l t l i ~a n d profcctc~clhy a lit.l~calc n p v d cr~till>osr.tlo r tIi[~usnlirf\o f ~ d r ~ n t l c a l c ~ ~ p ~ o r n(cornpate crs w ~ t hf:~g t-2n) Thr cornplelt. n ~ ~ r l c t r r n Il.;~I000 ~ ~ i ni n i Iorlg, hut I n thp Intact p a r l ~ c l c~t 1% trrlrlrd w n t l i ~ na rcluglrly s p h c r ~ r ai.nvclrrpc l ,ibout 680 n n i I n ti~;lme,ler ( A , 13. I ' r i ~ l r t r - % y Ur N C W r ~ g l c y ,C', crrurtr,sp 1% A. ) C;lbb\.)

Chapter

1

Strn~ctureand

Composition of Viruses

Viral Morphology

called rn/lstrmrrs (Figs. 1-1 A and 1-2A,R), which tlrr held togcthur by nnncovaI C ' I ~ L ~ O I I ~ S Witli~n . an infected ccll, thc cnpscimcrs u n d ~ r g i sclt-assembly l to form tht*c a p s ~ d'The manner of assembly 1s strictly defined by the nature of the bonds Curmed between ~ndividualcapsomers, which imparts symmetry. to the caj2sid Qrily two kinds of syrnmctry have been recognized, cubical (icosahcdlral) and 11~elical(Fig. 1 -2A,B)

7

Icosahedral Symmetry The cubic symmetry Cni~ndin viruses is b;lst.d o n that of an icosahedron, nnr of the five classical "Platonic solicis" nl geornctry An icosaliedrcrn has 12 verticcs (corners), 30 edges, and 20 faces, cach an cqirilateral triangle. I t has axes of two-, three-, and fivefold rc)taiional symmetry, passing thrc~ugliits edges, faces, and vertices, respective1 y (Fig. 1-3A-C) l'he icosahedron is the optimum solution to the problem of constructing, Crom repeating subunits, a strong structure to enclose a maximum voIurne Before icnsahedrons were discovered in viruses the same principles were applied by the architect Buckminster FuIlcr to the construction of icosaliedral buildings ("geodesic domes"). An object with icosahedral symmetry necd not appear angular in outline; the virions of r n a ~ ~animal y vlauses with icosahedral symmetry appear spherical with a bumpy stlrface. Only certain arrangements ol the capsomers can f i t into the faces, edges, and vertices of the viral icosahedron. The capsomers on the faces and edges of adenovirus particles, for exampIe, bond to six neighboring capsomers and are called hexnnrers; those at the verfices bond to five neighbors and are called ~u:ufamcvs(Figs. 1-1A and 1 -2A). In virions of some viruses both hexarners and pentamers consist of the same polypeptide(s); in those of olher viruses they are formed Crom different polypeptides. The arrangements of capsorners on the capsids of virions of three small icosahedral vlruses arc shown in Fig. 1-3D-F.

Nigh- Resolution Strsrcturc

external

domarn

I:t.nturrs of vrrrcm structure, exctnpl~frcdt-rp adenuvirus (A), tobaccn mr-rsa~c vrrus (R). anri rnfIt~c.nza A virus 11). ( A ) Icosahedral strc~cturc of an adrnov~rusvlrlr)n hl! hcwnn

Fig. 1-2

(c,

rapstrmc7rs art. tr~mersof ~hc.$nnlc3polypeptide, c i ~ s t ~ n ~ u r s has r d "per~pentclnal" l or "gloup elf nrlic." by tllt>rrlocatin11In Ilic capsid. Thc pcntnn h s c 15 a pe7rtlarncrc ~ artother f ~olypcptrde,the frbc.~ 1% a trrnlcr of a third pr,lypc.piidr (13) Tlic qtrttcturr rrl helical nucleocaps~dswa5 f i r d c,lucldnlt~d hy \["dies 111 a ~ionrnvrlcrpcdpllant vlrrls, tr~baciornrlalrc vlsrls, but the prrtlciples apply to anrn~nlvlrusrs w a ~ l hcIrcaI i nuclcr~capstds,all tri wilrch arcbcnvcloprd I n tclhacco mosalc \,rlr~s,.I srng3c polypeptldc Inrrnq a rapsr~nor,and 2130 cap\r>mcr\ awrrnble In a h e l ~ xThe 6 kb RNA fi~1701~itlit5 rn '1 grr~ovcon llrr ~ n n e part r of eacti cap.;r~rnc~r. and 1s w o u r ~ dto I n r n ~ a hclix the v ~ r ~ o n (C . )S l r ~ ~ c t ~or lr vrrrt~tl c 01 l n f l u r n ~ aA vrrrls All ar~rrnal whrch carlt3nd5thr Icnl:th x-~ru\c,.;w81lh 11r.llr-al nr~clrocipsidand stlrnc* o f thosr rwth a n rcosaliedral capstd are envrlrrpcd. -The, nurlcc,c.~ys~dswrlh Elclrcal syn~rnctryarc long and thin (scc 171~.I-IC and 28-11 and In rtlfll~~.n/n A V I I L ~ S lctular B l o l o ~ yc ~ Anrinal f Virtrst~s"(n P Napik, r r l ), p S Il n Srgrnc.ntcd jienuone, 2 mcilrrulcs 01 l~ncars\RNA, minus senw or arnb~sc.nscl; "sk~ckyc'r1d5" allr~cvc~rcular~/aiion Sejit~~cn~ gtlntlmry, cd 10, 1 0 , rir 12 niolccr~lrsof 1111t.ar dsRNA 13il'lr>ad genome, d ~ r r i r rc~fI~nears\RNA, plu5 crnse, lipdingen-br)nderl at 5' cnds. lern1111aIrt~tium~dancy. 11oIIi0' tcrii~lnlp o l y a t l ~ ~ i ~ y l ~ l l t . d , Ixrlli 5' cr~d.;c ~ y p c c l Clrr ular ssRNA, rnlnlt.; wnsc

--n

1-2-----

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-------_____- -Chapter 3 Structure and Composilion of Viruses

7'lit. s ~ z cof viral JJNA grnomcs r a n ~ e sfrorii 3.2 k ~ t ( l l ) f l /11?t?$ ~ r ~ ( k l l / ~ )f, ~ the r hc~~adnaviruscs, to cluer 200 khp COI thc lar-gchl of the &DNA herpesviruses a n d poxvirusvs As 1 kilobasc (kb) or 1 kbp ct~nlainsrhnough genetic inlormatiori to code lor cibt~ut one avercige-sized prnte~n,i t can be sun-r~isedthat viral DNAs contain roughly hetwctn 4 anci 200 genrs, coding for some 4 to 200 pruteins. Itowever, the relntfonsh~ybctwccn any particular nuclcntide sequt3nce and its protei~lproduct is not su straightforward. First, the DNA oi most of the larger v i r u s ~ s ,like that of mammalian cells, contains what appears to be redundant information, in the form of ( I ) repeat sequences and (2) irtfvor~r;, that is, regions which arc noncoding and are spliced nut from the primary RNA transcr~ptto form the mRNA. On the other hand, a single such primary RNA transcript may be spliced or cIeaved in several different ways to vield several dist~nctmRNAs, each of which Inay be translated into a diiferent protein Furkhermure, a given DNA or mRNA sequence may be read in u p to three diffcrenf rend~n,pjrnrnes, glving rise to two or three proteins with different ammo acld sequences. En additivn, either or both strands of doublestrarldcd viral 13NA may be transcnbed, in a leftward or a rightward direcllon. Viral D N A s contain several other kinds of noncoding sequences, some of which are corrserlsrrs S L ~ ~ U P I I C Ewhich S tend tn be conserved through cvulutinn because they serve vital functions, including RNA pnlymerase recognition codons for translation, termination sites and promoters, enhancers, in~tiat~on codons, and RNA splice sites.

RNA The genome of RNA viruses may be single-s!ra nded or double-stranded. MJh~lrsome genomes occur as a single molecule., others are sr,gme~~ted. Arenavirrls gcnomes consist nf 2 segments, bunyavi~usgenomes of 3, orthornyxcrvlrus elf 7 or 8 (rn different genera), and reovlrtrs of 10, 1I , or 12 (in different gw7wa). Each or the molecules is uniqere (often a single "gcne"). Except for the very small circular ssRNA of heyatitls D virus (the structure of which resembles that of viroids of plants), no animal virus RNA genome is a covalently linked circle I4owever, tlre ssl