Basic Virology 3rd Edition

8/10/2019 Basic Virology 3rd Edition

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Basic Virology

Third

Edition

Edward K. Wagner

Department of Molecular Biology and Biochemistry

University of California Irvine

Mart inezJ. Hewlett

Department of Molecular and Cellular Biology

University of Arizona

David C. Bloom

Department of Molecular Genetics and Microbiology

University of Florida

David Camerini

Department of Molecular Biology and Biochemistry

University of California Irvine

Blackwell

Publishing


2/16

Brief Contents

Preface xxi

Acknowledgments xx ix

P A R T I V I R O L O G Y A N D V I R A L D IS E A S E 1

Chapter 1 Intro duct ion Th e Impact of Viruses on O ur View of Life 3

Chapter 2 An Ou tline of Virus Replication and Viral Pathogenesis 15

Chapter 3 Virus Disease in Population s and Individual Animals 27

Chapter 4 Patterns of Some Viral Diseases of H um ans 41 *

PART I I BASIC PROPE RTIES OF VIRUSES A N D V IR U S -

CELL INT ER AC TIO N 63

Chapter 5 Virus Struc ture and Classification 65

Chapter 6 The Beginning and End of the Virus Replication Cycle 79

Chapter 7 Ho st Im m une Response to Viral Infection - Th e Na ture of the Vertebrate

Imm une Response 97

Chapter 8 Strategies to Protect Against and Co mb at Viral Infection 119

PART I I I W O R K IN G W IT H V IRUS 145

Chapter 9 Visualization and Enu me ration of Virus Particles 147

Chapter 10 Replicating and Me asuring Biological Activity of Viruses 155

Chapter 11 Physical and Chemical M anipu lation of the Structural Com pon ents of

Viruses 173

Chapter 12 Characterization of Viral Products Expressed in the Infected Cell 193

Chapter 13 Viruses Use Cellular Processes to Express their Genet ic

Information 213

P AR T IV R E P L I C A T I O N P A T T E R N S O F S P E C I F I C

VIRUSES 243

Chapter 14 Replication of Positive-sense RN A Viruses 245

Chapter 15 Replication Strategies of RNA Viruses Requ iring RNA -directed m RNA

Transcriptio n as the First Step in Viral Gene Expression 273

Chapter 16 Replication Strategies of Small and Medium -sized D N A Viruses 303


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4/16

Contents

Preface xxi

Preface to the second edition xxii

Preface to the third editio n xxii

Text organization xxiii

Specific features of this text designed to aid instructors and

students in pursuin g topics in greater depth xxvi

Dept h of coverage xxvi

Sources for further study xxvi

The Intern et xxvii

Chap ter outlines xxvii

Case studies xxvii

Review mate rial xxvii

Glossary xxvii

Acknowledgments xxix

PART I

CHAPTER 1

VIRO LOG Y AN D V IRAL DISEASE 1

Introduc tion - The Impact of Viruses on Ou r View of Life 3

Th e science of virology 3

The effect of virus infections on the host organism and populations

viral pathogenesis, virulence, and epidemiology 4

Th e interaction between viruses and their hosts 6

Th e history of virology 7

Examples of the impact of viral disease on hum an history 8

Examples of the evolutionary impact of the virus-host

interaction 9

Th e origin of viruses 9

Viruses have a constructive as well as destructive impact on

society 12

Viruses are not the smallest self-replicating path ogen s 13

Que stions for Cha pter 1 14

CHAPTER 2

An Outline of Virus Replication and Viral Pathogenesis

Virus replication 15

Stages of virus replication in the cell 17

Pathogenesis of viral infection 19

Stages of virus-induced pathology 19

15


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VI I I

CONTENTS

CHAPTER 3

CHAPTER 4

Initial stages of infection - entry of the virus into the host 20

Th e incuba tion period and spread of virus throug h the host 21

Multiplication of virus to high levels

occurrence of disease

symptoms 23

The later stages of infection

the imm une response 24


virus spread to the next

individual 24


fate of the host 24

Questions for Chapter 2 25

Virus Disease in Popu lations and Individual Animals 27

Th e nature of virus reservoirs 27

Some viruses with huma n reservoirs 28

Some viruses with verteb rate reservoirs 30

Viruses in popula tions 30

Viral epidemiology in small and large popula tions 30

Factors affecting the control of viral disease in populations 33

Anim al models to study viral pathogenesis 34

A mouse model for studying poxvirus infection and spread 35

Rabies: where is the virus durin g its long incubation period? 37

Herpes simplex virus latency 37

Mu rine models 39

Rabbit models 40

Guinea pig models 40


Patterns o f Some Viral Diseases of Humans 41

The dynamics of hum an-viru s interactions 42

The stable association of viruses with their natural host places

specific constraints on the nature of viral disease and mode of

persistence 42

Classification of human disease-causing viruses according to

virushost dynam ics 44

Viral diseases leading to persistence of the virus in the host are

generally associated with viruses having long associations with

hum an populations 44

Viral diseases associated with acute, severe infection are

suggestive of zoonoses 48

Patte rns of specific viral diseases of hu m ans 49

Acu te infections followed by virus clearing 49

Colds and respiratory infections 49

Influenza 49

Variola 49

Infection of an accidental target tissue leading to permane nt

dam age despite efficient clearing 50

Persistent viral infections 50

Papilloma and polyomavirus infections 50

Herpesvirus infections and latency 52

Ot her complications arising from persistent infections 52

Viral and subviral diseases with long incuba tion periods 53

Rabies 53


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CONTENTS IX

PART II

CHAPTER 5

CHAPTER 6

CHAPTER 7

HIV-AIDS 53

Prion diseases 54

Some viral infections targetin g specific organ systems 54

Viral infections of nerve tissue 54

Examples of viral encep halitis with grave progno sis 55

Rabies 55

Herpes encephalitis 55

Viral encepha litis with favorable prognosis for recovery 56

Viral infections of the liver (viral hepatitis ) 56

Hepatitis A 57

Hepatitis B 57

Hepatitis C 57

Hepatitis D 57

Hepatitis E 58


Problems for Part I 59

Add itional Reading for Part I 61

BASIC PROPERTIES OF VIRUSES A N D

V I R U S C E L L I N T E R A C T I O N

63

Virus Structure and Classification 65

The features of virus 65

Viral genomes 69

Viral capsids 69

Viral envelopes 72

Classification schemes 72

Th e Baltim ore scheme of virus classification 75

Disease-based classification schemes for viruses 75

Th e virosphere 77

Que stions for Chap ter 5 78

The Beginning and End o f the Virus Replication Cycle 79

Ou tline of the virus replication cycle 79

Viral entry 80

Animal virus entry into cells the role of the cellular receptor 80

Mech anisms of entry of nonenve loped viruses 83

En try of enveloped viruses 84

Entry of virus into plant cells 85

Injection of bacteriophage DNA into scherichia coli 87

Nonspecific methods of introd ucing viral genomes into cells 89

Late events in viral infection: capsid assembly and virion release 89

Assembly of helical capsids 89

Assembly of icosahedral capsids 92

Generation of the virion envelope and egress of the enveloped

virion 93

Question s for Chap ter 6 96

Host Immune Response to Viral Infection - The Nature of the

Verteb rate Imm une Response 97

The innate imm une response - early defense against pathogens 98

Toll-like receptors 99


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CONTENTS

Defensins 99

Th e adaptive imm un e response and the lymp hatic system 100

Tw o pathways of helper T response - the fork in the road 101

The immunological structure of protein 102

Role of the antigen-presenting cell in initiation of the immune

response 104

Clonal selection of im mu ne reactive lympho cytes 107

Immu ne memory 108

Co mp lem ent-m ediate d cell lysis 108

Con trol and dysfunction of imm unity 108

Specific viral responses to host immu nity 109

Passive evasion of immunity antigenic drift 110

Passive evasion of immunity internal sanctuaries for

infectious virus 110

Passive evasion of immunity imm une tolerance 110

Active evasion of imm unity - imm unosuppression 111

Active evasion of imm unity - blockage of M H C antigen

presentation 111

Con sequences of imm un e suppression to virus infections 112

Measurem ent of the imm une reaction 112

Measurem ent of cell-mediated (T-cell) imm unity 112

Measurement of antiviral antibody 112

Enzym e-linked imm uno sorb ent assays (ELISAs) 113

Neu tralization tests 114

Inhibition of hemagg lutination 114

Complement fixation 115

Questions for Chap ter 7 ^117

C H A P T E R 8 Strategies to Protect Against and Com bat Viral Infection 119

Vaccination

induction of immunity to prevent virus

infection 120

An tiviral vaccines 120

Smallpox and the history of vaccination 120

Ho w a vaccine is produced 122

Live-virus vaccines 122

Killed-virus vaccines 123

Reco mb inant virus vaccines 124

Capsid and subu nit vaccines 124

DN A vaccines 125

Edible vaccines 125

Problem s with vaccine prod uctio n and use 125

Eu kary otic cell-based defenses against virus replication 126

Interferon 126

Ind uctio n of interferon 127

Th e antiviral state 128

Me asurem ent of interferon activity 128

O th er cellular defenses against viral infection 130

Small RN A-based defenses 130

Enzym atic modification of viral genom es 131

Antiviral drugs 131


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CONTENTS

X I

PART

III

CHAPTER9

CHAPTER

1

Targeting antiviral drugsto specific featuresof the virus

replication cycle

131

Acyclovir

and the

herpesviruses

132

Blocking influenza virus entryandvirus maturation 132

Chemotherapeutic approachesfor HIV 134

Multiple drug therapies toreduceoreliminate mutationto

drug resistance

134

Other approaches

135

Bacterial antiviral systems restriction endonucleases 135

QuestionsforChapter 8 136

Problems

for

Part

II 139

Additional Reading

for

Part

II 143

WORKING WITH VIRUS 145

VisualizationandEnumerationofVirus Particles 147

Using

the

electron microscope

to

study

and

count viruses

147

Counting (enumeration)

of

virions with

the

electron

microscope

149

Atomic force microscopy

a

rapid

and

sensitive meth od

for

visualization

of

viruses

and

infected cells, potentially

in

real

time

151

Indirect methods for coun ting virus particles 152

Questions forChapter 9 154

Replicatingand Measuring Biological ActivityofViruses 155

Cell culture techniques

156

Maintenanceof bacterial cells 156

Plant cell cultures 156

Culture

of

animal

and

human cells

157

Maintenance

of

cells

in

culture

157

Types

of

cells

157

Lossof contact inhibition ofgrowth andimmortalizationof

primary cells 159

The outcome

of

virus infection

in

cells

160

Fate

of

the virus

160

Fate

of

the cell following virus infection

162

Cell-mediated maintenanceof the intra-and intercellular

environment 162

Virus-mediated cytopathology changes

in the

physical

appearance

of

cells

163

Virus-mediated cytopathology changesin thebiochemical

propertiesofcells 163

Measurement

of

the biological activity

of

viruses

164

Quantitative measure

of

infectious centers

164

Plaque assays

164

Generation of transformed cell foci 165

Use of virus titerstoquantitatively control infection conditions 166

Examples

of

plaque assays

167

Statistical analysis

of

infection

168


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X I I CONTENTS

CHAPTER 11

CHAPTER 12

Dilution endpo int methods 169

The relation between dilution endpoint and infectious units of

virus 169

Ques tions for Chap ter 10 170

Physical and Chemical Manipulation of the Structural

Com ponents of Viruses 173

Viral structural proteins 173

Isolation of structural proteins of the virus 174

Size fractionation of viral structu ral prote ins 176

Det erm ining the stoichiometry of capsid proteins 177

The poliovirus capsid - a virion with equimolar capsid

proteins 178

Analysis of viral capsids that do not contain equimolar numbers

of proteins 179

Characterizing viral genomes 179

Sequen ce analysis of viral genom es 180

Mea suring the size of viral genomes 184

Direct measure of DNA genome lengths in the electron

microscope 185

Rate zonal sedimentation and gel electrophoresis for measuring

viral geno me size 185

The polymerase chain reaction detection and characterization of

extremely small quantities of viral genomes or transcripts 187

Real time PCR for precise quantitative measures of viral

DNA 189

PCR detection of RNA 190

PC R as an epidemiological tool 190

Que stions for Chap ter 11 191

Characterization of Viral Products Expressed in the Infected

Cell 193

Cha racteri zation of viral prote ins in the infected cell 193

Pulse labeling of viral proteins at different times following

infection 194

Use of imm une reagents for study of viral proteins 195

Work ing with antibodies 196

Dete ction of viral proteins using immuno fluorescence 198

Related methods for detecting antibodies bound to

antigens 201

Detecting and characterizing viral nucleic acids in infected

cells 205

Dete cting the synthesis of viral genomes 205

Characterization of viral mR NA expressed durin g infection 205

In situ hybridization 207

Further characterization of specific viral mRNA

molecules 209

Use of microarray technology for getting a complete picture of the

events occurring in the infected cell 210

Questions for Chap ter 12 212


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CONTENTS

XIII

CHAPTER 13

PART IV

CHAPTER 14

Viruses Use Cellular Processes to Express Their Genetic

Information 213

Prokaryotic DNA replication is an accurate enzymatic model for

the process generally 21 5

Th e replication of eukaryotic DN A 216

Th e replication of viral DN A 21 7

Th e effect of virus infection on host D N A replication 217

Expression of mR NA 217

Prokaryotic transcription 219

Prokaryotic RNA polymerase 219

The prokaryotic promoter and initiation of

transcription 220

Con trol of prokaryotic initiation of transcription 220

Term ination of prokaryotic transcription 221

Eukaryotic transcription 221

Th e promo ter and initiation of transcription 221

Con trol of initiation of eukaryotic transcription 223

Processing of precursor mR NA 224

Visualization and location of splices in eukaryotic

transcripts 226

Posttranscriptional regulation of eukaryotic mRNA

function 231

Virus-induced changes in transcription and posttranscriptional

processing 232

Th e mechanism of protein synthesis 232

Euk aryotic translation 233

Prokaryotic translation 234

Virus-ind uced changes in translation 236


Problems for Part III 239

Additional Reading for Part III 241

R E P L I C A T I O N

VIRUSES 243

PATTERNS OF SPECIF IC

245

eplication of Positive-sense RNA Viruses

RNA viruses general considerations 246

A general picture of RNA -directed RNA replication 246

Replication of positive-sense RNA viruses whose genomes are

translated as the first step in gene expression 248

Positive-sense RNA viruses encoding a single large open reading

frame 249

Picornavirus replication 249

The poliovirus genetic map and expression of poliovirus

proteins 249

Th e poliovirus replication cycle 252

Picornavirus cytopatholog y and disease 254

Flavivirus replicatio n 25 6

Positive-sense RNA viruses encoding more than one translational

reading frame 257


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XIV CONTENTS

Two viral mRNAs are produced in different amounts during

togavirus infections 258

Th e viral genome 258

Th e virus replication cycle 258

Togavirus cytopatholog y and disease 262

A somewhat more complex scenario of multiple translational

reading frames and subgenomic mRNA expression: coronavirus

replication 263

Coron avirus replication 264

Cyto patho logy and disease caused by coronaviruses 266

Replication of plant viruses with RNA genomes 267

Viruses with one genome segment 268

Viruses with two genom e segments 268

Viruses with three genom e segments 269

Replication of bacteriophage with RNA genomes 269

Regulated translation of bacteriophage mR NA 269


C H A PT

R 1 5 Replication Strategies o f RNA Viruses Requiring RNA-directed

mRNA Transcription as the First Step in Viral Gene

Expression 273

Replication of negative-sense RNA viruses with a monopartite

genome 275

Replication of vesicular stomatitis virus - a model for

Mononegavirales 275

Vesicular stomatitis virus virion and genom e 275

Generation, capping, and polyadenylation of mR NA 276

Gen eration of new negative-sense virion RNA 278

Mech anism of host shutoff by vesicular stomatitis virus 279

Cyto patho logy and diseases caused by rhabdoviruses 280

Paramyxoviruses 280

Pathogenesis of paramyxoviruses 280

Filoviruses and their pathogenesis 28 2

Bornaviruses 282

Influenza viruses - negative-sense RN A viruses with a

multipartite genome 283

Involvem ent of the nucleus in flu virus replication 284

Generation of new flu nucleocapsids and maturation of the

virus 285

Influenza A epidemics 285

Other negative-sense RNA viruses with multipartite

genomes 288

Bunyaviruses 288

Virus structure and replication 288

Pathogenesis 291

Arenaviruses 291

Virus gene expression 292

Pathogenesis 292

Viruses with double-stranded RNA genomes 292


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CONTENTS

XV

CHAPTER 16

CHAPTER 17

Reovirus structu re 292

Reovirus replication cycle 294

Pathogenesis 295

Subviral pathog ens 29 5

Hep atitis delta virus 296

Viroids 297

Prions 298

Que stions for Ch apter' 15 301

Replication Strategies of Small and Medium-Sized DNA

Viruses 303

DNA viruses express genetic information and replicate their

genomes in similar, yet distinct, ways 304

Papovavirus replication 30 5

Replication of SV40 virus - the model polyomavirus 305

Th e SV40 genome and genetic map 309

Productive infection by SV40 310

Abortive infection of cells nonpermissive for SV40

replication 312

Replication of papillomaviruses 31 4

The HPV -16 genome 316

Virus replication and cytopatholog y 316

Replication of adenoviruses 319

Physical properties of adenovirus 319

Capsid structure 319

Th e adenovirus genome 319

Th e adenovirus replication cycle 319

Early events 31 9

Adenovirus DN A replication 321

Late gene expression 321

VA transcription and cytopathology 321

Transfo rmation of nonperm issive cells by adenovirus 323

Replication of some single-stranded D N A viruses 32 3

Replication of parvoviruses 323

Dependovirus DNA integrates in a specific site in the host cell

genome 324

Parvoviruses have potentially exploitable therapeutic

applications 325

DN A viruses infecting vascular plants 325

Geminiviruses 325

Single-stranded DNA bacteriophage OX174 packages its genes

very comp actly 326


Replication of Some Nuclear-Replicating Eukaryotic DNA Viruses

wi th Large Genomes 331

Herpesvirus replication and latency 332

Th e herpesviruses as a group 332

Gen etic complexity of herpesviruses 33 3


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XVI CONTENTS

Co mm on features of herpesvirus replication in the host 33 3

Th e replication of the prototypical alpha-herpesvirus -

HSV 334

The HSV virion 334

Th e viral genome 334

HS V productive infection 338

HS V latency and LAT 347

HS V transcription during latency and reactivation 348

Ho w do LA T and other specific HS V genes function - may be

to accom mo date reactivation? 350

EBV latent infection of lymphocytes, a different set of problems

and answers 351

Pathology of herpesvirus infections 354

Herpesviruses as infectious co-carcinogens 354

Baculovirus, an insect virus with important practical uses in

molecular biology 355

Virion structure 355

Viral gene expression and genom e replication 356

Pathogenesis 356

Imp ortance of baculoviruses in biotechnolo gy 356


C H A P T E R 1 8 Replication of Cytoplasmic DNA Viruses and Large

Bacteriophages 359

Poxviruses DNA viruses that replicate in the cytoplasm of

eukaryotic cells 360

The pox virion is complex and contains virus-coded transcription

enzymes 360

T he poxvirus replication cycle 361

Early gene expression 363

Geno me replication 363

Interm ediate and late stages of replication 363

Pathogenesis and history of poxvirus infections 36 4

Is smallpox virus a poten tial biological terror weapon? 364

Replication of large DN A-con taining bacteriophages 365

Co mp onen ts of large DN A-co ntaining phage virions 365

Replication of phage T7 367

The genome 367

Phage-controlled transcription 367

Th e practical value of T 7 367

T4 bacterioph age: the basic mod el for all DN A viruses 367

The T4 genome 368

Regulated gene expression dur ing T 4 replication 369

Capsid ma turatio n and release 370

Replication of phage

X:

a simple model for latency and

reactivation 370

The phage Xgenome 372

Phage

X

gene expression imm ediately after infection 37 2

Biochemistry of the decision between lytic and lysogenic

infection in

E. coli

375


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CONTENTS

XVII

CHAPTER 19

CHAPTER 20

CHAPTER 21

A group of algal viruses shares features of its genome structure with

poxviruses and bacteriophages 376


Retroviruses: Conv erting RNA to DNA 381

Retrovirus families and their strategies of replication 382

Th e molecular biology of retrovirus 383

Retrovirus structural proteins 383

Th e retrovirus genom e 384

Gene tic maps of representative retroviruses 386

Replication of retroviruses: an outline of the replication

process 386

Initiation of infection 386

Capsid assembly and ma turation 389

Action of reverse transcriptase and RNase-H in synthesis of

cDNA 389

Virus gene expression, assembly, and ma turatio n 391

Transcription and translation of viral mRN A 391

Capsid assembly and morphog enesis 391

Mechan isms of retrovirus transformation 392

Transformation through the action of

viral oncogene

a

subverted cellular growth control gene 392

Oncornavirus alteration of normal cellular transcriptional control

of growth regulation 393

Oncornavirus transformation by growth stimulation of

neighboring cells 395

Cellular genetic elements related to retroviruses 395

Retrotransposons 396

Th e relationship between transposable elements and viruses 397

Qu estions for Cha pter 19 397

Human Immunodeficiency Virus Type 1 (HIV-1) and Related

Lentiviruses 399

HI V- 1 and related lentiviruses 399

The origin of HIV -1 and AIDS 399

HI V- 1 and lentiviral replication 400

Destruction of the imm une system by HIV-1 406


Hepadnaviruses: Variations on the Retrovirus Theme 413

Th e virion and the viral genom e 413

Th e viral replication cycle 41 5

The pathogenesis of hepatitis B virus 415

A plant hepadna virus : cauliflower mosaic virus 416

Geno me structure 416

Viral gene expression and genom e replication 416

Th e evolutionary origin of hepadnaviruses 417


Problems for Part IV 421

Add itional Reading for Part IV 429


15/16

XVII I

CONTENTS

PART V

CHAPTER 22

CHAPTER 23

CHAPTER 24

V I R U S E S : N E W A P P R O A C H E S A N D N E W

PROBLEMS 433

The Mo lecular Genetics of Viruses 435

M utatio ns in genes and resulting changes to proteins 437

Analysis of mu tation s 43 8

Complementation 438

Recombination 439

Isolation of mutan ts 440

Selection 440

HS V thymidine kinase - a portable selectable marker 440

Screening

441

441 tool kit for molecular virologists

Viral genomes 441

Locating sites of restriction endonuclease cleavage on the viral

genome - restriction mapp ing 442

Clon ing vectors 44 3

Cloning of fragments of viral genomes using bacterial

plasmids 444

Cloning using phage X 449

Clonin g single-stranded DN A with bacteriophage M 13 451

DN A animal virus vectors 451

RN A virus expression systems 45 3

Defective virus particles 45 4

Directed mutagenesis of viral genes

Site-directed mutagenesis 45 6

Generation of recombinant viruses

Bacterial artificial chromosomes


454

456

458

Molecu lar Pathogenesis 463

An introd uctio n to the study of viral pathogenesis 46 3

Animal models 464

Choo sing a model: natural host vs. surrogate models 464

Dev elopm ent of new models: transgenic animals 464

Hyb rid models: the SC ID-h u mouse 464

Considerations regarding the hum ane use of animals 465

Meth ods for the study of pathogenesis 466

Assays of virulenc e 46 6

Analysis of viral spread within the host 46 7

Resolving the infection to the level of single cells 47 0

Characterization of the host response 470

Imm unolog ical assays 470

Use of transgenic mice to dissect critical components of the host

im mu ne response that mo dulate the viral infection 471

Question for Chap ter 23 471

Viral Bioinformatics and Beyond

Bioinformatics 473

Bioinformatics and virology 47 3

Biological databases 47 4

473


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CONTENTS X IX

CHAPTER 25

APPENDIX

Primary databases 47 4

Secondary databases 475

Com posite databases 475

Oth er databases 476

Biological applications 47 6

Similarity searching tools 476

Protein functional analysis 478

Sequ ence analysis ,478

Structural modeling 478

Structural analysis 47 8

Systems biology and viruses 479

Viral internet resources 481


Viruses and the Future - Problems and Promises 485

Clouds on the horizon emerging disease 48 5

Sources and causes of emergen t virus disease 488

Th e threat of bioterrorism 489

What are the prospects of using medical technology to eliminate

specific viral and othe r infectious diseases? 49 0

Silver linings viruses as therape utic agents 49 0

Viruses for gene delivery 49 1

Using viruses to destroy other viruses 49 3

Viruses and nanotechnology 49 3

Th e place of viruses in the biosphere 49 4

W hy study virology? 494


Problems for Part V 49 7

Additional Reading for Part V 499

Resource Center 501

Books of historical and basic value 501

Books on virology 501

Mo lecular biology and biochem istry texts 503

Detailed sources 50 3

Sources for experimental protocols 503

Th e Internet 504

Virology sites 504

Important websites for organizations and facilities of

interest 505

Technical Glossary 507

Index 533

Basic Virology 3rd Edition

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