Virology: Molecular Biology and Pathogenesis

VIROLOGY

MOLECULAR BIOLOGY AND PATHOGENESIS

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V ROLOGY

MOLECULAR BIOLOGY AND PATHOGENESIS

LEONARD C. NORKIN

Department of Microbiology

University of Massachusetts

Amherst, Massachusetts

ASM

PRESS

Washington, DC

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Copyright © 2010 ASM Press

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Library of Congress Cataloging-in-Publication Data

Norkin, Leonard C.

Virology : molecular biology and pathogenesis / Leonard C. Norkin.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-55581-453-3 (hardcover : alk. paper) 1. Virology—Textbooks.

2. Molecular virology—Textbooks. 3. Virus diseases—

Pathogenesis—Textbooks. I. Title.

[DNLM: 1. Viruses—pathogenicity. 2. Genome, Viral. 3. Virus Diseases—etiology.

4. Viruses—genetics. QW 160 N841v 2010]

QR360.N67 2010

616.9′101—dc22

2009036895

10 9 8 7 6 5 4 3 2 1

All rights reserved

Printed in Canada

Cover and interior design: Susan Brown Schmidler

Illustrations: Lineworks, Inc.

Cover illustration: Structure and molecular organization of a Sindbis virus particle.

Sindbis virus is a member of the togavirus family of enveloped plus-strand RNA viruses.

The surface features of the particle were determined by cryo-electron microscopy,

which yielded hundreds of highly detailed, two-dimensional images, from which

a three-dimensional image was generated using powerful computer programs.

A cross-section through the particle, showing the envelope glycoproteins

(blue), the lipid bilayer (green), the nucleocapsid (red), the mixed RNA-protein

region (orange), and the genomic plus-strand RNA (magenta), is superimposed on the

three-dimensional image. Protein structures were solved by X-ray crystallography,

and then fitted into the cryo-EM structure. See Figure 8.1 in the book for the complete

image. Adapted from W. Zhang et al., J. Virol. 76:11645–11648, 2002, with permission.

I dedicate this book to my wife, Arline; my sons, Dave and Mike, and their wives,

Mina and Debbie; and my grandchildren, Luke, Maya, and Theo.

‘‘Human subtlety will never devise an invention more beautiful, more simple

or more direct than does Nature, because in her inventions, nothing is lacking

and nothing is superfluous.’’

Leonardo da Vinci (1452–1519)

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vii

Contents

Preface xix

PART I Introduction 1

1 A Selective History on the Nature of Viruses 3

Introduction 3

The Early Years: Discoverers and Pioneers 4

The First Stirrings of the Molecular Era 7

The Phage Group 10

Phage Growth: Eclipse and Replication 11

Defining Viruses 15

Are Viruses Alive? 16

Origin of Viruses 17

The Modern Era of Animal Virology 17

2 Biosynthesis of Viruses: an Introduction to Virus

Classification 20

T-Even Bacteriophages as a Model System 20

T-Even Phage Structure and Entry 22

Sequence of Phage Biosynthetic Events 24

Phage Protein Synthesis 24

RNA Metabolism in Infected Cells 25

Assembly of Progeny Phages 27

Packaging DNA within the Phage Particle 28

Unique Features of T-Even Phages 30

Modified Bases 30

Regulated Gene Expression 30

Phage Release: Lysozyme and the rII Region 32

Bacteriophage Lambda (λ): Lysogeny and Transduction 33

Some Final Comments on Bacteriophages 39

viii CONTENTS

Introduction to the Animal Viruses 39

Animal Virus Structure 39

Entry of Animal Viruses 42

The Families of Animal Viruses: Principles of Classification 45

Viral Genetic Systems: the Baltimore Classification Scheme 45

3 Modes of Virus Infection and Disease 50

Introduction 50

Portals of Entry 50

Routes of Dissemination 54

Hematogenous and Neural Dissemination 54

The Placenta and the Fetus 60

Acute versus Persistent Infections 63

Acute Infections 64

Persistent Infections 66

Slow Infections 66

Chronic Infections 68

Latent Infections 74

Transmissible Spongiform Encephalopathies: Prions 76

4 Host Defenses and Viral Countermeasures 80

Introduction 80

Overview of Defenses 81

Physical Barriers against Infection 82

The Innate Immune System 82

Cytokines: the IFNs 84

Cytokines: TNF-α, Some Other Cytokines, and Inflammation 88

Macrophages, Neutrophils, NK Cells, and Antibody-Dependent

Cellular Cytotoxicity 89

The Complement System 95

Viral Evasion of Innate Immunity 98

Evasion of IFNs 98

Evasion of Cytokines 100

Evasion of NK Cells and ADCC 101

Evasion of Complement 102

APOBEC3G and the HIV Vif Protein 103

The Adaptive Immune System 103

Antibodies and B Cells 104

Antibody Diversity 106

Viral Evasion of Antibodies 110

Cell-Mediated Immunity 113

Antigen Presentation by MHC Class I Molecules 119

Antigen Presentation by MHC Class II Molecules 119

The Rationale for MHC Restriction 121

Activation of Th Cells: Dendritic Cells and B Cells 124

Activation of B Cells 126

Activation of CTLs 128

Mechanism of Action of CTLs 129

CON T E N T S ix

T Cells and Antiviral Cytokines 131

Viral Evasion of Cell-Mediated Immunity 132

Inhibition of Antigen Presentation to CTLs 132

Inhibition of Antigen Presentation to Helper T Cells 134

Inhibition of Apoptosis 134

Immunological Memory 136

Self Tolerance 137

The Immune System in Disease 140

Immunopathology 140

Autoimmune Disease 141

PART II Virus Replication and Pathogenesis 147

RNA Viruses: Double Stranded 149

5 Reoviruses 149

Introduction 149

Structure, Binding, Entry, and Uncoating 150

Reovirus Binding and Entry into the Cell 150

Structure, Uncoating, and Entry into the Cytoplasm 154

The Reovirus Genome: Transcription and Translation 156

The Particle-Associated RNA Polymerase 156

The Segmented Reovirus Genome 158

Conversion of ISVPs to Cores 161

Replication and Encapsidation of the Reovirus Genome 165

Synthesis of Double-Stranded RNA 165

Assembly of Progeny Subviral Particles and Encapsidation of RNA Segments 166

Reoviruses and IFN 166

Primary versus Secondary Transcription 167

Final Virus Assembly 168

Pathogenesis 168

Orthoreoviruses 168

Rotaviruses 168

Coltiviruses 169

RNA Viruses: Single Stranded 171

6 Picornaviruses 171

Introduction 171

Structure, Binding, and Entry 172

Picornavirus Structure 172

Rhinovirus Receptor and Binding: the Canyon Hypothesis 173

The Poliovirus Receptor 177

Receptors for Coxsackieviruses and Other Enteroviruses 179

Receptors for FMDVs 180

Poliovirus and Rhinovirus Entry: Some General Points 181

Poliovirus Entry 181

x CONTENTS

Human Rhinovirus Entry 183

Poliovirus and Rhinovirus Entry: Why the Differences? 184

Translation 184

Translation: Part I 184

Translation: a Digression 187

The RNA Phages 187

Picornaviruses versus RNA Phages: Why the Differences? 191

Translation: Part II 192

Transcription and Genome Replication 194

Assembly and Maturation 198

Medical Aspects 200

Poliovirus 200

Rhinoviruses: the Common Cold 203

Coxsackievirus and Echovirus 205

Viral Hepatitis: Hepatitis A 205

7 Flaviviruses 207

Introduction 207

Structure and Entry 208

Replication 209

Assembly and Release 209

Historic Interlude: Identification of Hepatitis C Virus 212

West Nile Virus: an Emerging Virus 213

Epidemiology and Pathogenesis 214

General Principles of Arthropod Transmission 214

Infection, Dissemination, and Determinants of Pathogenesis 215

Hemorrhagic Fever Viruses: Yellow Fever and Dengue Viruses 217

Encephalitis Viruses: Japanese Encephalitis, St. Louis Encephalitis,

and West Nile Viruses 218

Japanese Encephalitis and St. Louis Encephalitis Viruses 218

West Nile Virus 220

Hepatitis C Virus 220

8 Togaviruses 224

Introduction 224

Structure and Entry 225

Transcription, Translation, and Genome Replication 228

Assembly and Maturation 231

Epidemiology and Pathogenesis 232

Alphaviruses That Cause Encephalitis: Eastern, Western, and

Venezuelan Equine Encephalitis Viruses 232

Alphaviruses That Cause Arthritis: Chikungunya, Ross River, and Sindbis Viruses 232

Rubella Virus 232

CON T E N T S xi

9 Coronaviruses 235

Introduction 235

Structure 236

Entry 237

Genome Organization and Expression 238

Coronavirus mRNAs and Their Translation 238

Coronavirus Transcription 243

Coronavirus Recombination 247

Coronavirus Reverse Genetics 248

Assembly and Release 250

Medical Aspects 251

SARS 252

10 Rhabdoviruses 261

Introduction 261

Structure 262

Entry 263

Genome Organization, Expression, and Replication 264

The General Transcriptional Strategy of Viruses That Contain Negative-Sense

RNA Genomes 264

Gene Organization and Transcription 264

Replication 267

Assembly and Release 268

Medical Aspects 269

Cytopathic Effects 269

VSV 270

Rabies Virus 270

11 Paramyxoviruses 273

Introduction 273

Structure 274

Entry 276

Syncytium Formation 279

Genome Organization, Expression, and Replication 279

Genome Organization and Transcription 279

Replication 281

Assembly and Release 282

Medical Aspects 282

Measles 282

Clinical Conditions 282

SSPE 285

Where Did Measles Come from? 288

Measles Vaccine 289

Mumps 290

Parainfluenza Viruses 290

Respiratory Syncytial Virus 291

xii CONTENTS

HMPV 292

Hendra, Nipah, and Menangle Viruses 294

CDV 295

12 Orthomyxoviruses 296

Introduction 296

Structure 298

Entry 299

Endocytosis and Intracellular Trafficking of Influenza Virus-Containing Endosomes 300

Viral Membrane Fusion: the HA Protein 302

Release of the Genome from the Envelope: the M2 Protein 307

Transport of vRNPs to the Cell Nucleus 308

Genome Organization, Transcription, and Replication 311

Genome Organization and Transcription 311

Why Does Influenza Virus Transcription Really Occur in the Nucleus? 317

Replication 317

The NS1 and PB1-F2 Proteins 318

Assembly and Release 322

Assembly of vRNPs 322

Two Issues Regarding Intracellular Targeting of Viral Components 322

Transport of vRNPs from Nucleus to Cytoplasm 322

Apical Targeting of Virus Components and Final Virus Assembly 323

Encapsidating Eight Distinct Genomic Segments 325

Release: the Influenza Virus NA Protein 325

Medical Aspects 325

Pathology and Clinical Syndromes 325

The Flu Pandemic of 1918 326

Origin of Epidemic and Pandemic Strains: Antigenic Drift and Antigenic Shift 328

Virulence of the 1918 Pandemic Influenza Virus: Opening Pandora’s Box 333

Influenza Drugs and Vaccines 336

Avian Influenza and Humans 337

Preparedness for an Outbreak of Avian Influenza 341

13 Miscellaneous RNA Viruses 346

Introduction 346

Arenaviruses 347

Lassa Fever Virus: an Early Emerging Virus 348

LCMV and Immunopathology 348

The Ambisense Arenavirus Genome 349

Bunyaviruses 350

Sin Nombre and Hantaan Viruses 351

The Tripartite Bunyavirus Genome 351

Bornaviruses 352

BDV and Human Neuropsychiatric Disease 352

Bornavirus Genomes and Their Nuclear Transcription and Replication 354

Caliciviruses 355

Norwalk Virus (Norovirus) 355

Calicivirus Replication 356

Astroviruses 356

CON T E N T S xiii

Hepatitis E-Like Viruses 357

Filoviruses 358

Structure and Replication 358

Marburg and Ebola Viruses 358

Is Ebola Virus the “Andromeda Strain?” 361

DNA Viruses: Single Stranded 362

14 Parvoviruses 362

Introduction 362

Parvovirus Structure, Binding, and Entry 363

Parvovirus Genomes 365

Replication of Parvovirus Single-Stranded DNA 367

A General Model: the “Rolling Hairpin” 368

Encapsidation of Progeny DNA 371

Genome Organization and Expression 374

The Dependovirus Life Cycle 374

Integration of Dependovirus Genomes 375

Medical Aspects 376

DNA Viruses: Double Stranded 378

15 Polyomaviruses 378

Introduction 378

Structure 380

Entry and Uncoating 382

Genome Organization and Expression 385

Genome Organization 385

The Regulatory Region 386

T Antigen in Temporal Regulation of Transcription 390

Splicing Pattern of Viral mRNA 394

DNA Replication 395

Late Proteins and Assembly 399

T Antigens and Neoplasia 401

SV40 in Its Natural Host 410

SV40 in Humans 411

JCV and BKV in Humans 414

KI, WU, and Merkel Cell Human Polyomaviruses 415

SV40-Based Gene Delivery Vectors 418

16 Papillomaviruses 419

Introduction 419

Structure 420

Entry and Uncoating 421

xiv CONTENTS

Genome Organization and Expression 424

Replication 429

Release and Transmission 432

Cell Transformation and Oncogenesis: Cervical Carcinoma 433

Molecular Mechanisms 433

Stages of Cancer Development 439

Tissue Microenvironment 439

Treatment and Prevention 441

HPV Vaccine To Prevent Cervical Cancer 441

Oropharyngeal Cancer 442

17 Adenoviruses 444

Introduction 444

Structure 446

Entry and Uncoating 448

Genome Organization and Expression 452

E1A and E1B Proteins in Replication and Neoplasia 456

Shutoff of Host Protein Synthesis 458

DNA Replication 460

Assembly 462

Evasion of Host Defenses 464

Clinical Syndromes 465

Recombinant Adenoviruses 466

Gene Therapy 466

Cancer Therapies 467

Vaccines: HIV and Influenza Virus 469

18 Herpesviruses 471

Introduction 471

Structure 473

Entry and Uncoating 475

Genome Organization and Expression 481

DNA Replication 487

Assembly, Maturation, and Release 488

Assembly of Procapsids 488

Encapsidation of DNA 490

Final Assembly and Release 491

Latent Infection and Immune Evasion 493

HSV 494

EBV 499

HCMV 503

Clinical Syndromes 506

HSV 507

EBV 508

HCMV 512