Table Of Contents:
Acknowledgments xix
Organization of This Book xxiii
I The Science of Virology 1(56)

Foundations of Virology 2(22)

Luria's Credo 3(1)

Virus Prehistory 3(5)

Viral Infections in Antiquity 3(1)

The First Vaccines 4(2)

Microorganisms as Pathogenic Agents 6(2)

The Discovery of Viruses 8(3)

The First Viruses 8(2)

Identification of Human Viruses 10(1)

The Definitive Properties of Viruses 11(4)

The Structural Simplicity of Viruses 11(1)

The Intracellular Parasitism of Viruses 11(4)

Viruses Defined 15(1)

Cataloging of Diverse Animal Viruses 16(4)

Many Sizes and Shapes Produced by Evolution 16(3)

Genetic Content 19(1)

Capsid Symmetry 19(1)

Enveloped or Naked Particles 20(1)

Virion Enzymes 20(1)

Unifying Principles 20(1)

A Common Strategy 20(1)

Highlights of Virus Strategies Outlined in This Book 21(1)

References 21(3)

Virus Cultivation, Detection, and Genetics 24(33)

Introduction 25(1)

Cultivation of Viruses 25(4)

Cell Culture 25(2)

Embryonated Eggs 27(1)

Laboratory Animals 28(1)

Detection of Viruses in the Host 29(13)

Measurement of Infectious Units 29(4)

Measurement of Virus Particles and Their Components 33(7)

The One-Step Growth Cycle 40(2)

Genetic Analysis of Viruses 42(13)

Classical Genetic Methods 42(2)

Engineering Mutations into Viruses 44(7)

Engineering Viral Genomes: Viral Vectors 51(4)

Perspectives 55(1)

References 55(2)
II Molecular Biology 57(420)

Virus Structure 58(42)

Introduction 59(6)

Functions of the Virion 59(1)

Nomenclature 60(2)

Methods for Studying Virus Structure 62(3)

Building a Protective Coat 65(22)

Helical Structures 66(1)

Capsids or Nucleocapsids with Icosahedral Symmetry 66(18)

Complex Viruses 84(3)

Packaging the Nucleic Acid Genome 87(2)

Direct Contact of the Genome with Proteins of the Outer Shell 87(1)

Packaging by Specialized Virion Proteins 88(1)

Packaging by Cellular Proteins 88(1)

Viruses with Envelopes 89(5)

Viral Envelope Components 90(2)

Simple Enveloped Viruses: Direct Contact of External Proteins with the Capsid or Nucleocapsid 92(1)

Enveloped Viruses with Additional Protein Layers 92(2)

Other Components of Virions 94(2)

Virion Enzymes 94(1)

Other Viral Proteins 95(1)

Cellular Macromolecules 96(1)

Perspectives 96(1)

References 97(3)

Virus Attachment to Host Cells 100(32)

Introduction 101(1)

Protection and Release of Genetic Material 102(1)

Finding the Right Cells To Infect 102(1)

The Architecture of Cell Surfaces 102(4)

Extracellular Matrix: Components and Biological Importance 103(1)

Properties of the Plasma Membrane 103(2)

Cell Membrane Proteins 105(1)

Interaction of Viruses with Cell Receptors 106(22)

General Principles 106(6)

Identification of Viral Receptors on Cells 112(11)

How Virions Attach to Receptors 123(5)

Perspectives 128(1)

References 129(3)

Virus Entry into Cells 132(30)

Introduction 133(1)

Uptake of Macromolecules by Cells 134(3)

The Plasma Membrane Is a Semipermeable Barrier 134(1)

Cells Take Up Macromolecules by Phagocytosis and Endocytosis 134(2)

Cell Membranes Fuse during Endocytosis 136(1)

Mechanisms of Virus Entry into Cells 137(15)

Uncoating at the Plasma Membrane 137(5)

Virus Entry via the Endocytic Pathway 142(5)

Entry of Nonenveloped Viruses into Cells 147(4)

Cellular Molecules That Play Roles in Virus Uncoating 151(1)

Transport of the Viral Genome into the Nucleus 152(7)

The Cellular Pathway of Protein Import into the Nucleus 152(4)

Import of DNA Genomes 156(1)

Import of the Retroviral Genome into the Nucleus 157(2)

Import of Influenza Virus RNP into the Cell Nucleus 159(1)

Perspectives 159(1)

References 160(2)

Genome Replication and mRNA Production by RNA Viruses 162(36)

Introduction 163(1)

Mechanisms of Viral RNA Synthesis 164(21)

RNA-Dependent RNA Polymerases 164(4)

Accessory Proteins in RNA-Dependent RNA Synthesis 168(4)

The Nature of the RNA Template 172(2)

Initiation and Elongation 174(9)

Cellular Sites of Viral RNA Synthesis 183(1)

Unique Mechanisms of mRNA and Genome Synthesis of the Hepatitis Delta Satellite Virus 184(1)

The Switch from mRNA Production to Genome RNA Synthesis 185(5)

Regulation of Initiation: Different Polymerase Specificities 187(1)

Suppression of Intergenic Stop-Start Reactions by Nucleocapsid Protein 188(1)

Antitermination and Different RNA Polymerases 189(1)

Suppression of Termination Caused by a Stem-Loop Structure 189(1)

Different Templates Used for mRNA Synthesis and Genome Replication 189(1)

Suppression of Polyadenylation 190(1)

Origins of Diversity in RNA Viruses 190(4)

Misincorporation of Nucleotides 190(1)

Segment Reassortment and RNA Recombination 191(1)

RNA Recombination Leading to the Production of Pathogenic Viruses 192(1)

RNA Recombination Leading to the Production of Defective-Interfering RNAs 192(1)

RNA Editing 193(1)

Perspectives 194(1)

References 194(4)

Reverse Transcription and Integration: Hallmarks of the Retroid Viruses 198(38)

Retroviral Reverse Transcription 199(15)

Introduction 199(1)

The Pathway of Retroviral Reverse Transcription 200(7)

General Properties and Structure of Retroviral Reverse Transcriptases 207(5)

Other Examples of Reverse Transcription 212(2)

Retroviral DNA Integration 214(10)

Introduction 214(1)

Pathway of Retroviral Integration 214(5)

Integrase Structure and Mechanism 219(5)

Hepadnaviral Reverse Transcription 224(8)

Introduction 224(1)

Pathway of Reverse Transcription 225(7)

Perspectives 232(1)

Comparison of Systems 232(1)

References 233(3)

Transcription Strategies: DNA Templates 236(50)

Introduction 237(1)

Properties of Cellular and Viral Transcription Systems 238(14)

Cellular Transcription Systems Used by Viruses 238(1)

Production of Viral DNA Templates Transcribed by Cellular RNA Polymerases 238(2)

Transcription by RNA Polymerase II 240(12)

Transcription of Viral DNA Templates by the Cellular Machinery Alone 252(1)

Viral Proteins That Regulate Transcription by RNA Polymerase II 253(24)

Patterns of Regulation by Viral Proteins 253(1)

Autoregulation by the Human Immunodeficiency Virus Type 1 Tat Protein 253(8)

The Transcriptional Cascades of DNA Viruses 261(16)

A Viral DNA-Dependent RNA Polymerase 277(1)

Transcription of Viral Genes by RNA Polymerase III 278(2)

Transcription of the Adenoviral VA-RNA Genes 279(1)

Virus-Specific Applications of Cellular Transcription Components 280(1)

Inhibition of the Cellular Transcription Machinery in Virus-Infected Cells 281(1)

Perspectives 281(1)

References 282(4)

Genome Replication Strategies: DNA Viruses 286(44)

Introduction 287(2)

DNA Synthesis by the Cellular Replication Machinery: Lessons from Simian Virus 40 289(10)

Eukaryotic Replicons 289(3)

Cellular Replication Proteins and Their Functions during Simian Virus 40 DNA Synthesis 292(7)

Mechanisms of Viral DNA Synthesis 299(16)

Priming and Elongation 299(4)

Viral Replication Origins and Their Recognition 303(8)

Viral DNA Synthesis Machinery 311(2)

Resolution and Processing of Viral Replication Products 313(2)

Mechanisms of Exponential Viral DNA Replication 315(5)

Induction of Synthesis of Cellular Replication Proteins by Viral Gene Products 315(3)

Synthesis of Large Sets of Viral Replication Proteins 318(1)

Viral DNA Replication Independent of Cellular Proteins 318(1)

Delayed Synthesis of Virion Structural Proteins 318(1)

Inhibition of Cellular DNA Synthesis 319(1)

Localization of Replicating Viral DNA to Specialized Intracellular Sites 319(1)

Limited Replication of Viral DNA 320(3)

Replication as Part of the Cellular Genome: Integrated Parvoviral DNA 320(1)

Regulation of Replication via Different Viral Origins: Epstein-Barr Virus 321(1)

Controlled and Exponential Replication from a Single Origin: the Papillomaviruses 322(1)

Origins of Genetic Diversity in DNA Viruses 323(3)

Fidelity of Replication by Viral DNA Polymerases 323(1)

Recombination of Viral Genomes 324(2)

Perspectives 326(1)

References 327(3)

Processing of Viral Pre-mRNA 330(40)

Introduction 331(2)

Covalent Modification during Viral Pre-mRNA Processing 333(18)

Capping the 5' Ends of Viral mRNA 333(4)

Synthesis of 3' Poly (A) Segments of Viral mRNA 337(2)

Splicing of Viral Pre-mRNA 339(6)

Alternative Splicing of Viral Pre-mRNA 345(3)

Interactions Between Polyadenylation and Splicing in Viral Gene Expression 348(3)

Editing of Viral mRNAs 351(1)

Export of Viral and Cellular RNAs from the Nucleus 351(7)

The Cellular Export Machinery 352(1)

Export of Viral mRNA 353(5)

Posttranscriptional Regulation of Viral or Cellular Gene Expression by Viral Proteins 358(5)

Temporal Control of Viral Gene Expression 358(3)

Inhibition of Cellular mRNA Production by Viral Proteins 361(2)

Regulation of Turnover of Viral and Cellular mRNAs in the Cytoplasm 363(2)

Regulation of mRNA Stability by a Viral Protein 363(1)

Regulation of mRNA Stability in Transformation 364(1)

Perspectives 365(1)

References 366(4)

Translational Control of Viral Gene Expression 370(32)

Introduction 371(1)

Mechanisms of Eukaryotic Protein Synthesis 372(12)

General Structure of Eukaryotic mRNA 372(1)

The Translational Machinery 372(1)

Initiation 373(10)

Elongation and Termination 383(1)

The Diversity of Viral Translation Strategies 384(7)

Polyprotein Synthesis 384(2)

Leaky Scanning 386(2)

Reinitiation 388(1)

Suppression of Termination 388(2)

Ribosomal Frameshifting 390(1)

Regulation of Translation during Viral Infection 391(7)

Inhibition of Translation as a Cellular Defense against Viral Infection 392(3)

Regulation of eIF4F Activity 395(3)

Perspectives 398(1)

References 399(3)

Intracellular Transport of Viral Components: Prelude to Assembly 402(36)

Introduction 403(1)

Assembly within the Nucleus 404(2)

Import of Viral Proteins for Assembly 404(2)

Assembly at the Plasma Membrane 406(23)

The Cellular Pathway by Which Viral Membrane Proteins Are Transported to the Plasma Membrane 406(12)

Viral Proteins in the Secretory Pathway 418(3)

Sorting of Viral Proteins in Polarized Cells 421(3)

Inhibition of Transport of Cellular Proteins by Viral Infection 424(1)

Signal Sequence-Independent Transport of Viral Proteins to the Plasma Membrane 425(4)

Interactions with Internal Cellular Membranes 429(2)

Localization of Viral Proteins to Compartments of the Secretory Pathway 429(1)

Localization of Viral Proteins to the Nuclear Membrane 430(1)

Transport of Viral Genomes to Assembly Sites 431(2)

Genome RNA Transport from the Nucleus to the Cytoplasm 432(1)

RNA Transport from the Cytoplasm to the Plasma Membrane 432(1)

Perspectives 433(1)

References 434(4)

Assembly, Exit, and Maturation of Progeny Virions 438(39)

Introduction 439(1)

Methods of Studying Virus Assembly and Egress 440(3)

Structural Studies of Virus Particles 440(1)

Visualization of Assembly and Exit by Electron Microscopy 441(1)

Biochemical and Genetic Analysis of Assembly Intermediates 441(2)

Methods Based on Recombinant DNA Technology 443(1)

Assembly of Protein Shells 443(9)

Formation of Structural Units 443(3)

Capsid and Nucleocapsid Assembly 446(2)

Self-Assembly and Assisted Assembly Reactions 448(4)

Selective Packaging of the Viral Genome and Other Virion Components 452(8)

Concerted or Sequential Assembly 452(1)

Recognition and Packaging of the Nucleic Acid Genome 452(8)

Incorporation of Virion Enzymes and Other Nonstructural Proteins 460(1)

Acquisition of an Envelope 460(3)

Sequential Assembly of Internal Components and Budding from a Cellular Membrane 460(1)

Coordination of the Assembly of Internal Structures with the Acquisition of the Envelope 461(2)

Release of Virus Particles 463(4)

Release of Nonenveloped Viruses 463(1)

Assembly at Internal Membranes: the Problem of Exocytosis 464(3)

Maturation of Progeny Virions 467(5)

Proteolytic Processing of Virion Proteins 467(3)

Other Maturation Reactions 470(2)

Cell-to-Cell Spread 472(1)

Perspectives 473(1)

References 473(4)
III Pathogenesis and Control 477(272)

Virus Offense Meets Host Defense 478(40)

The Host Defense Against Viral Infections 479(5)

Primary Defenses 479(1)

Immune Defenses 480(4)

The Innate Immune Response 484(9)

Cytokines 484(1)

Interferons 485(4)

Complement 489(3)

Collectins 492(1)

NK Cells 492(1)

The Adaptive Immune Response 493(18)

General Features 493(3)

Cells of the Adaptive Immune System 496(6)

Antigen Presentation and Activation of Immune Cells 502(4)

The Cell-Mediated Adaptive Response 506(2)

The Antibody Response 508(3)

Perspectives 511(4)

References 515(3)

Patterns of Infection: a Delicate Balance 518(34)

Introduction 519(1)

Infection Strategies 519(1)

Life Cycles and Patterns of Viral Infections 519(1)

Initiating an Infection 520(11)

Basic Requirements 520(1)

Tropism 521(1)

Successful Infections Must Evade Host Defenses 521(10)

Many Other Variables Govern the Result of Infection 531(1)

Acute Infections 531(4)

Definition and Requirements 531(2)

Acute Infections Present Common Public Health Problems 533(1)

Defense against Acute Infections 534(1)

Multiple Acute Infections in a Single Host 534(1)

Pathogenic Effects of an Acute Infection 535(1)

Persistent Infections 535(5)

Definition and Requirements 535(1)

Infection of Tissues with Reduced Immune Surveillance 536(1)

Direct Infection of the Immune System Itself 537(1)

Two Viruses That Cause Persistent Infections 538(2)

Latent Infections 540(6)

An Extreme Variation of the Persistent Infection 540(1)

Two Viruses That Produce Latent Infections 540(6)

Slow Infections 546(3)

Sigurdsson's Legacy: Icelandic Sheep and Fatal Degenerative Diseases 546(1)

Slow Viruses and "Unconventional Agents" 546(3)

Other Patterns of Viral Infections 549(1)

Abortive Infections 549(1)

Transforming Infections 550(1)

Perspectives 550(1)

References 550(2)

Viral Transformation and Oncogenesis 552(42)

Introduction 553(9)

Properties of Transformed Cells 554(3)

Control of Cell Growth and Division 557(5)

Oncogenic Viruses 562(9)

Discovery of Oncogenic Viruses 562(2)

Viral Genetic Information in Transformed Cells 564(5)

The Origin and Nature of Viral Transforming Genes 569(2)

Functions of Viral Transforming Proteins 571(1)

Viral Transformation by Activation of Cellular Signal Transduction Pathways 571(11)

Viral Mimics of Cellular Signaling Molecules 572(4)

Virus-Specific Signal Transduction Molecules 576(1)

Alteration of the Expression or Activity of Cellular Signal Transduction Proteins 576(6)

Viral Transformation via Cell Cycle Control Pathways 582(7)

Abrogation of Restriction Point Control Exerted by the Rb Protein 582(1)

Inhibition of Negative Regulation by Rb-Related Proteins 583(3)

Production of Virus-Specific Cyclins 586(1)

Inhibition of p53 Functions 586(3)

Other Mechanisms of Viral Transformation and Oncogenesis 589(2)

Nontransducing Complex Oncogenic Retroviruses: Tumorigenesis with Very Long Latency 589(1)

Hepadnaviral Oncogenesis 590(1)

"Hit-and-Run" Transformation by Herpes Simplex Viruses? 590(1)

Perspectives 591(1)

References 592(2)

Viral Pathogenesis 594(36)

Introduction 595(1)

Viral Dissemination in the Host 595(19)

Viral Entry 595(5)

Viral Spread 600(6)

Tissue Invasion 606(3)

Tropism 609(3)

Virus Shedding and Transmission 612(2)

Viral Virulence 614(5)

Measuring Viral Virulence 615(1)

Genetic Determinants of Virulence 615(4)

Injury Induced by Viruses 619(6)

Direct Effects of Primary Infection by Cytolytic Viruses 619(1)

Pathogenic Effects of Noncytolytic Viruses 620(1)

Immunopathology: Indirect Effects of Viral Infection 620(5)

Host Susceptibility to Viral Disease 625(1)

Genetic Determinants of Susceptibility 625(1)

Nongenetic Determinants of Susceptibility 626(1)

Perspectives 626(1)

References 627(3)

Multiple Facets of Human Immunodeficiency Virus Pathogenicity 630(32)

Introduction 631(1)

Worldwide Scope of the Problem 631(1)

HIV Is a Lentivirus 632(6)

Discovery and Characterization 632(2)

Distinctive Features of the HIV Replication Cycle and the Roles of Auxiliary Proteins 634(4)

Cellular Targets 638(2)

Routes of Transmission 640(2)

Sources of Virus Infection 640(1)

Modes of Transmission 640(1)

Mechanics of Spread 641(1)

The Course of Infection 642(2)

Patterns of Virus Appearance and Immune Cell Indicators of Infection 642(1)

Variability of Response to Infection 643(1)

Origins of Cellular Immune Dysfunction 644(2)

CD4+ T Lymphocytes 644(1)

CD8+ T Lymphocytes 644(1)

Monocytes and Macrophages 644(1)

B Cells 645(1)

Natural Killer Cells 645(1)

Autoimmunity 645(1)

Immune Response to HIV 646(3)

Humoral Responses 646(2)

The Cellular Immune Response 648(1)

Summary: the Critical Balance 648(1)

Dynamics of HIV-1 Replication in AIDS Patients 649(1)

Effects of HIV on Different Tissues and Organ Systems 650(4)

Lymphoid Organs 650(2)

The Nervous System 652(2)

The Gastrointestinal System 654(1)

Other Organ Systems 654(1)

HIV and Cancer 654(3)

Kaposi's Sarcoma 654(1)

B-Cell Lymphomas 655(1)

Anogenital Carcinomas 656(1)

Prospects for Treatment and Prevention 657(3)

Antiviral Drugs and Therapies 657(2)

Vaccine Development 659(1)

Perspectives 660(1)

References 661(1)

Prevention and Control of Viral Diseases 662(54)

Introduction 663(1)

Vaccines: the Proven Best Defense against Viruses 664(2)

Smallpox: a Historical Perspective 664(1)

Large-Scale Vaccination Programs Can Be Dramatically Effective 664(2)

Preparation of Vaccines 666(12)

The Fundamental Challenge 666(1)

Vaccine Basics 666(4)

Three Types of Vaccines 670(8)

New Vaccine Technology 678(5)

Viral Vectors 678(1)

DNA Vaccines 678(4)

Vaccine Delivery Technology 682(1)

Immunotherapy 682(1)

Antiviral Drugs: Small Molecules That Block Virus Replication 683(19)

Paradox: So Much Knowledge, So Few Antivirals 683(1)

Historical Perspective 683(1)

Discovering Antiviral Compounds 684(1)

Screening for Antiviral Compounds 685(2)

Designer Antivirals and Computer-Based Searching 687(3)

The Difference between "R" and "D" 690(1)

Examples of Commercially Available Antiviral Drugs for Viruses other than HIV 691(5)

New Targets for Antiviral Drugs 696(3)

Antiviral Gene Therapy and Transdominant Inhibitors 699(2)

Resistance to Antiviral Drugs 701(1)

HIV and AIDS 702(10)

Examples of Drugs Approved by the Food and Drug Administration for Treatment of HIV Infection 702(5)

The Problem of Drug Resistance and the Use of Combination Therapy To Combat HIV Infection 707(2)

Combination Therapy 709(2)

The Quest for an AIDS Vaccine 711(1)

Perspectives 712(1)

References 712(4)

Virus Evolution and the Emergence of New Viruses 716(33)

Virus Evolution 717(12)

Virus Evolution Is Contemporary 717(1)

How Do Viruses Evolve? 717(5)

The Origin of Viruses 722(5)

Evolution Is Constrained by the Fundamental Properties of Viruses 727(2)

Emerging Viruses 729(13)

The Spectrum of Host-Virus Interactions 729(6)

Known Viruses Can Expand Their Niche because of Changing Host Populations and Environment 735(4)

Known Viruses Can Expand Their Host Range or Pathogenicity by Mutation or Recombination 739(2)

Some Emergent Viruses Are Truly Novel 741(1)

A Paradigm Shift in Diagnostic Virology 742(1)

Perceptions and Possibilities 742(4)

Infectious Agents and Public Perceptions 742(1)

What Next? 743(3)

Perspectives 746(1)

References 746(3)
Appendix: Structure, Genome Organization, and Infectious Cycles of Selected Animal Viruses Discussed in This Book 749(32)
Index 781