Nigel Dimmock is an internationally acclaimed virologist who has spent the major part of his career at the University of Warwick where he is an emeritus Professor. His main research interests are influenza virus and antiviral strategies.

Andrew Easton is a Professor of Virology at the University of Warwick. His research focuses on the molecular biology and pathogenesis of respiratory viruses, particularly respiratory syncytial virus and influenza virus and the control of translation of virus mRNA.

Keith Leppard is an Associate Professor (Reader) at the University of Warwick. His research focuses on adenoviruses: their replication, the effects of viral proteins on the host cell, and on the development of the virus as a gene delivery vehicle.

Preface xvii

About the companion website xix

PART I THE NATURE OF VIRUSES 1

Chapter 1 Towards a definition of a virus 3

1.1 Discovery of viruses 4

1.2 Multiplication of viruses 5

1.3 The virus multiplication cycle 6

1.4 Viruses can be defined in chemical terms 7

1.5 Multiplication of bacterial and animal viruses is fundamentally similar 10

1.6 Viruses can be manipulated genetically 11

1.7 Properties of viruses 11

1.8 Origin of viruses 12

Key points 12

Further reading 12

Chapter 2 The structure of virus particles 13

2.1 Virus particles are constructed from subunits 13

2.2 The structure of filamentous viruses and nucleoproteins 14

2.3 The structure is of isometric virus particles 15

2.4 Enveloped (membrane-bound) virus particles 24

2.5 Virus particles with head-tail morphology 27

2.6 Frequency of occurrence of different virus particle morphologies 28

2.7 Principles of disassemply: virus particles are metastable 28

Key points 29

Further reading 29

Chapter 3 Classification of viruses 30

3.1 Classification on the basis of disease 30

3.2 Classification on the basis of host organism 31

3.3 Classification on the basis of virus particle morphology 31

3.4 Classification on the basis of viral nucleic acids 32

3.5 Classification on the basis of taxonomy 34

3.6 Satellites, viroids and prions 35

Key points 37

Further reading 38

Chapter 4 The evolution of viruses 39

4.1 Mechanisms of virus evolution 40

4.2 The potential for rapid evolution: mutation and quasispecies 40

4.3 Rapid evolution: recombination 43

4.4 Rapid evolution: reassortment 43

4.5 Evolution to find a host, and subsequent co-evolution with the host 46

Key points 51

Questions 51

Further reading 51

Chapter 5 Techniques for studying viruses 52

5.1 Culturing wild virus isolates 52

5.2 Enumeration of viruses 54

5.3 Measuring infectious virus titres 55

5.4 Measuring physical virus titres 57

5.5 Detecting virus in a sample 58

5.6 Understanding virus replication cycles 62

5.7 Viral genetics and reverse genetics 63

5.8 Systems-level virology 63

Key points 65

Questions 65

Further reading 65

PART II VIRUS GROWTH IN CELLS 67

Chapter 6 The process of infection: I. Virus attachment and entry into cells 69

6.1 Infection of animal cells: the nature and importance of receptors 69

6.2 Infection of animal cells: enveloped viruses 73

6.3 Infection of animal cells: non-enveloped viruses 78

6.4 Infection of plant cells 80

6.5 Infection of bacteria 81

6.6 Infection of cells: post-entry events 82

6.7 Virus entry: cell culture and the whole organism 84

Key points 84

Questions 84

Further reading 85

Chapter 7 The process of infection: IIA. The replication of viral DNA 86

7.1 The universal mechanism of DNA synthesis 87

7.2 Replication of circular double-stranded DNA genomes 90

7.3 Replication of linear double-stranded DNA genomes that can form circles 93

7.4 Replication of linear double-stranded DNA genomes that do not circularize 96

7.5 Replication of single-stranded circular DNA genomes 100

7.6 Replication of single-stranded linear DNA genomes 100

7.7 Dependency versus autonomy among DNA viruses 103

Key points 103

Questions 103

Further reading 103

Chapter 8 The process of infection: IIB. Genome replication in RNA viruses 105

8.1 Nature and diversity of RNA virus genomes 106

8.2 Regulatory elements for RNA virus genome synthesis 106

8.3 Synthesis of the RNA genome of Baltimore class 3 viruses 111

8.4 Synthesis of the RNA genome of Baltimore class 4 viruses 111

8.5 Synthesis of the RNA genome of Baltimore class 5 viruses 115

8.6 Synthesis of the RNA genome of viroids and hepatitis delta virus 118

Key points 119

Questions 119

Further reading 119

Chapter 9 The process of infection: IIC. The replication of RNA viruses with a DNA intermediate and vice versa 121

9.1 The retrovirus replication cycle 122

9.2 Discovery of reverse transcription 122

9.3 Retroviral reverse transcriptase 123

9.4 Mechanism of retroviral reverse transcription 125

9.5 Integration of retroviral DNA into cell DNA 128

9.6 Production of retrovirus progeny genomes 130

9.7 Spumaviruses: retrovirus with unusual features 131

9.8 The hepadnavirus replication cycle 131

9.9 Mechanism of hepadnavirus reverse transcription 131

9.10 Comparing reverse transcribing viruses 134

Key points 134

Questions 134

Further reading 135

Chapter 10 The process of infection: IIIA. Gene expression in DNA viruses and reverse-transcribing viruses 136

10.1 The DNA viruses and retroviruses: Baltimore classes 1, 2, 6 and 7 137

10.2 Polyomaviruses 138

10.3 Papillomaviruses 142

10.4 Adenoviruses 144

10.5 Herpesviruses 147

10.6 Poxviruses 149

10.7 Parvoviruses 149

10.8 Retroviruses 150

10.9 Hepadnaviruses 153

10.10 DNA bacteriophages 154

Key points 154

Questions 155

Further reading 155

Chapter 11 The process of infection: IIIB. Gene expression and its regulation in RNA viruses 156

11.1 The RNA viruses: Baltimore classes 3, 4 and 5 157

11.2 Reoviruses 158

11.3 Picornaviruses 163

11.4 Alphaviruses 164

11.5 Coronaviruses 166

11.6 Negative sense RNA viruses with segmented genomes 169

11.7 Orthomyxoviruses 169

11.8 Arenaviruses 173

11.9 Negative sense RNA viruses with non-segmented, single stranded genomes: rhabdoviruses and paramyxoviruses 174

Key points 177

Questions 178

Further reading 178

Chapter 12 The process of infection: IV. The assembly of viruses 179

12.1 Self-assembly from mature virion components 180

12.2 Assembly of viruses with a helical structure 180

12.3 Assembly of viruses with an isometric structure 184

12.4 Assembly of complex viruses 187

12.5 Sequence-dependent and -independent packaging of virus DNA in virus particles 189

12.6 The assembly of enveloped viruses 190

12.7 Segmented virus genomes: the acquisition of multiple nucleic acid molecules 194

12.8 Maturation of virus particles 195

Key points 196

Questions 197

Further reading 197

PART III VIRUS INTERACTIONS WITH THE WHOLE ORGANISM 199

Chapter 13 Innate and intrinsic immunity 201

13.1 Innate immune responses in vertebrates – discovery of interferon 202

13.2 Induction of type 1 interferon responses 203

13.3 Virus countermeasures to innate immunity 207

13.4 TRIM proteins and immunity 209

13.5 Intrinsic resistance to viruses in vertebrates 210

13.6 Innate and intrinsic immunity and the outcome of infection 212

13.7 RNAi is an important antiviral mechanism in invertebrates and plants 212

13.8 Detecting and signalling infection in invertebrates and plants 214

13.9 Virus resistance mechanisms in bacteria and archaea 215

Key points 216

Questions 217

References 217

Chapter 14 The adaptive immune response 218

14.1 General features of the adaptive immune system 219

14.2 Cell-mediated immunity 221

14.3 Antibody-mediated humoral immunity 226

14.4 Virus evasion of adaptive immunity 232

14.5 Age and adaptive immunity 233

14.6 Interaction between the innate and adaptive immune systems 233

Key points 234

Questions 236

Further reading 236

Chapter 15 Interactions between animal viruses and cells 237

15.1 Acutely cytopathogenic infections 238

15.2 Persistent infections 238

15.3 Latent infections 241

15.4 Transforming infections 243

15.5 Abortive infections 243

15.6 Null infections 244

15.7 How do animal viruses kill cells? 244

Key points 246

Questions 247

Further reading 247

Chapter 16 Animal virus–host interactions 248

16.1 Cause and effect: Koch’s postulates 248

16.2 A classification of virus–host interactions 249

16.3 Acute infections 252

16.4 Subclinical infections 253

16.5 Persistent and chronic infections 254

16.6 Latent infections 256

16.7 Slowly progressive diseases 257

16.8 Virus-induced tumours 258

Key points 259

Questions 260

Further reading 260

Chapter 17 Mechanisms in virus latency 261

17.1 The latent interaction of virus and host 261

17.2 Gene expression and the lytic and lysogenic life of bacteriophage λ 263

17.3 Herpes simplex virus latency 270

17.4 Epstein-Barr virus latency 274

17.5 Latency in other herpesviruses 275

17.6 HIV-1 latency 277

Key points 277

Questions 278

Further reading 278

Chapter 18 Transmission of viruses 279

18.1 Virus transmission cycles 279

18.2 Barriers to transmission 281

18.3 Routes of horizontal transmission in animals 282

18.4 Vertical transmission 285

18.5 Vector-borne viruses and zoonotic transmission 287

18.6 Epidemiology of virus infections 289

18.7 Sustaining infection in populations 290

Key points 291

Questions 291

Further reading 291

PART IV VIRUSES AND HUMAN DISEASE 293

Chapter 19 Human viral disease: an overview 295

19.1 A survey of human viral pathogens 295

19.2 Factors affecting the relative incidence of viral disease 297

19.3 Factors determining the nature and severity of viral disease 299

19.4 Common signs and symptoms of viral infection 301

19.5 Acute viral infection 1: gastrointestinal infections 302

19.6 Acute viral infection 2: respiratory infections 304

19.7 Acute viral infection 3: systemic spread 306

19.8 Acute viral disease: conclusions 306

Key points 307

Questions 308

Further reading 308

Chapter 20 Influenza virus infection 309

20.1 The origins of human influenza viruses 309

20.2 Influenza virus replication 315

20.3 Influenza virus infection and disease 316

20.4 Virus determinants of disease 321

20.5 Host factors in influenza virus disease 322

20.6 The immune response and influenza virus 323

20.7 Anti-influenza treatment 324

Key points 325

Questions 326

Further reading 326

Chapter 21 HIV and AIDS 327

21.1 Origins and spread of the HIV pandemic 327

21.2 Molecular biology of HIV 330

21.3 HIV transmission and tropism 338

21.4 Course of HIV infection: pathogenesis and disease 339

21.5 Immunological abnormalities during HIV infection 342

21.6 Prevention and control of HIV infection 343

Key points 345

Questions 346

Further reading 346

Chapter 22 Viral hepatitis 347

22.1 The signs and symptoms of hepatitis 347

22.2 Hepatitis A virus infections 349

22.3 Hepatitis E virus infections 350

22.4 Hepatitis B virus infections 352

22.5 Hepatitis D virus infections 355

22.6 Hepatitis C virus infections 356

Key points 359

Questions 361

Further reading 361

Chapter 23 Vector-borne infections 362

23.1 Arboviruses and their hosts 362

23.2 Yellow fever virus 363

23.3 Dengue virus 367

23.4 Chikungunya virus 369

23.5 West Nile virus in the USA 372

Key points 375

Questions 375

Further reading 375

Chapter 24 Exotic and emerging viral infections 376

24.1 Ebola and Marburg viruses: emerging filoviruses 377

24.2 Hendra and Nipah viruses: emerging paramyxoviruses 381

24.3 SARS and MERS: emerging coronaviruses 383

24.4 Predicting the future: clues from analysis of the genomes of previously unknown viruses 386

Key points 386

Questions 386

Further reading 387

Chapter 25 Carcinogenesis and tumour viruses 388

25.1 Immortalization, transformation and tumourigenesis 389

25.2 Oncogenic viruses 390

25.3 Polyomaviruses, papillomaviruses and adenoviruses: the small DNA tumour viruses as experimental models 394

25.4 Papillomaviruses and human cancer 398

25.5 Polyomaviruses and human cancer 399

25.6 Herpesvirus involvement in human cancers 400

25.7 Retroviruses as experimental model tumour viruses 402

25.8 Retroviruses and naturally-occurring tumours 404

25.9 Hepatitis viruses and liver cancer 405

25.10 Prospects for the control of virus-associated cancers 406

Key points 407

Questions 408

Further reading 408

Chapter 26 Vaccines and immunotherapy: the prevention of virus diseases 409

26.1 The principles of vaccination 411

26.2 Whole virus vaccines 412

26.3 Advantages, disadvantages and difficulties associated with whole virus vaccines 415

26.4 Subunit vaccines 420

26.5 Advantages, disadvantages and difficulties associated with subunit vaccines 421

26.6 Considerations for the generation and use of vaccines 422

26.7 Adverse reactions and clinical complications with vaccines 423

26.8 Eradication of virus diseases by vaccination 425

26.9 Immunotherapy for virus infections 428

26.10 Adverse reactions and clinical complications with immunotherapy 429

Key points 429

Questions 430

Further reading 430

Chapter 27 Antiviral therapy 431

27.1 Scope and limitations of antiviral therapy 431

27.2 Antiviral therapy for herpesvirus infections 432

27.3 Antiviral therapy for influenza virus infections 434

27.4 Antiviral therapy for HIV infections 435

27.5 Antiviral therapy for hepatitis virus infections 439

27.6 Therapy for other virus infections 440

Key Points 441

Questions 441

Further Reading 442

Chapter 28 Prion diseases 443

28.1 The spectrum of prion diseases 443

28.2 The prion hypothesis 444

28.3 The aetiology of prion diseases 447

28.4 Prion disease pathogenesis 448

28.5 Bovine spongiform encephalopathy (BSE) 451

28.6 BSE and the emergence of variant CJD 453

28.7 Concerns about variant CJD in the future 454

28.8 Unresolved issues 455

Key points 456

Questions 456

Further reading 456

PART V VIROLOGY – THE WIDER CONTEXT 459

Chapter 29 The economic impact of viruses 461

29.1 The economics of virus infections of humans 462

29.2 The economics of virus infections of animals 464

29.3 The economics of virus infections of plants 466

29.4 The Netherlands tulip market crash 469

Key points 470

Further reading 470

Chapter 30 Recombinant viruses: making viruses work for us 472

30.1 Recombinant viruses as vaccines 473

30.2 Recombinant viruses for gene therapy 474

30.3 Retroviral vectors for gene therapy 476

30.4 Adenovirus vectors for gene therapy 478

30.5 Parvovirus vectors for gene therapy 480

30.6 Oncolytic viruses for cancer therapy 480

30.7 Recombinant viruses in the laboratory 482

Key points 482

Questions 482

Further reading 483

Chapter 31 Viruses: shaping the planet 484

31.1 Virus infections can give a host an evolutionary advantage 484

31.2 Endogenous retroviruses and host biology 485

31.3 Bacteriophage can be pathogenicity determinants for their hosts 488

31.4 Cyanophage impacts on carbon fixation and oceanic ecosystems 488

31.5 Virology and society: for good or ill 489

Key points 490

Questions 490

Further reading 490

Index 491

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