Papillomaviruses (eBook)

PREFACE 5
CONTENTS 6
LIST OF CONTRIBUTORS 15
Principles of Human Tumor Virology 18
1.1. Introduction 18
1.2. Precedents in Animals 18
1.3. Human Tumor Viruses 19
1.4. Mechanisms of Viral Tumorigenesis 22
1.5. Immunity and Tumor Viruses 23
1.6. Prospects for Prevention and Treatment 24
1.7. Conclusions 25
References 25
History of Papillomavirus Research 29
2.1. Introduction 29
2.2. The 1930s and 1940s: Biology of the Shope Papillomavirus and Other Animal Papillomaviruses 30
2.3. The 1950s and 1960s: Cell Differentiation and Virus Replication 32
2.4. The 1970s to the Early 1990s: Viral Genetics and the Emergence of HPV as a Medically Important Virus 33
References 38
Phylogeny and Typing of Papillomaviruses 45
3.1. Introduction 45
3.2. Papillomaviridae: A Taxon Separate from the Polyomaviruses 47
3.3. Novel Attempts to Improve the Nomenclature of Groups of Papillomavirus ( PV) Types 47
3.4. Papillomavirus Types, the Natural Taxonomic Entities in Molecular and Clinical Investigations 52
3.5. Papillomavirus Subtypes 52
3.6. Papillomavirus Variants 53
3.7. Papillomavirus Typing in Research and Clinical Practice 54
3.8. General Considerations Regarding the Evolution of Papillomaviruses 55
3.9. Evolution of Papillomaviruses: The Time Scale 56
3.10. Pathogenicity Versus Latency 57
References 58
The Differentiation-Dependent Life Cycle of Human Papillomaviruses in Keratinocytes 61
4.1. Introduction 61
4.2. Life Cycle of HPVs 61
4.3. Methods to Study the HPV Life Cycle 62
4.4. Genome Organization and Gene Products of HPVs 65
4.5. Control of HPV Transcription 68
4.6. Differentiation-Dependent Mechanisms to Regulate HPV DNA Replication 70
4.7. Roles of the HPV E6 and E7 Proteins in the Viral Life Cycle 71
4.8. Effects of HPVs on Epithelial Differentiation 73
4.9. Conclusion 74
References 74
Papillomavirus Structure and Assembly 84
5.1. Introduction 84
5.2. Structure Determination 85
5.3. L1 Monomer 87
5.4. Disulfide Bonds 88
5.5. Pentamer–Pentamer Contacts 89
5.6. Surface Loops and Epitopes 91
5.7. L1 Self-Assembly 92
5.8. Pseudovirion Synthesis 94
5.9. Role of L2 95
5.10. Nuclear Localization and DNA Binding of L1 and L2 96
5.11. Summary 98
References 98
Viral Entry and Receptors 104
6.1. Introduction 104
6.2. Binding to the Cell Surface 106
6.3. Contribution of L2 to Viral Entry 111
6.4. A Passage to Cytoplasm and Nucleus 111
6.5. Conclusion 116
References 117
Human Papillomavirus Transcription 123
7.1. Introduction 123
7.2. Overview of Viral Transcription in Productive Infections 126
7.3. Viral RNA Mapping in Warty Lesions 127
7.4. Organotypic Raft Cultures of Primary Human Keratinocytes as a Model System to Study HPVs 132
7.5. Where in the Stratified Squamous Epithelium Are E6 and E7 Proteins Expressed in Productively Infected Lesions? 135
7.6. Mechanisms That Control the Expression of the E6 and E7 Proteins 137
7.7. What Is the Role of E2? 139
7.8. Why Are There So Many Promoters and Spliced Transcripts? 140
7.9. Basis For HPV Oncogenesis 142
7.10. Concluding Remarks 145
References 145
DNA Replication of Papillomaviruses 159
8.1. Introduction 159
8.2. Assays for Replication of Viral DNA 160
8.3. Plasmid Maintenance 162
8.4. The Relationship Between DNA Replication and Morphological Transformation 162
8.5. The Basic Requirements for DNA Replication: E1, E2, and Ori 163
8.6. The Requirement for Cellular Factors in Viral DNA Replication 164
8.7. Description of the Parts 165
8.8. Understanding the E1 Protein 168
8.9. The Interaction Between E1 and Cellular and Viral Factors Involved in DNA Replication 174
8.10. A Conflict Between Specific and Nonspecific DNA- Binding Activities in E1 176
8.11. A Mechanism of Action for E2 178
8.12. The E1-E2 Complex is a Precursor for Formation of Larger E1 Complexes 178
8.13. The Viral DNA Replication Machinery as a Target for Small Molecule Intervention 180
References 182
Papillomavirus E5 Proteins 189
9.1. Introduction 189
9.2. The BPV1 E5 Protein 189
9.3. The BPV4 E5 Protein 194
9.4. The Human Papillomavirus E5 Proteins 195
9.5. Interaction of E5 Proteins with the Vacuolar H+- ATPase 197
9.6. E5 Proteins and Major Histocompatibility Antigen Expression 199
9.7. Effects of E5 Proteins on Apoptosis 200
9.8. Role of E5 Proteins in the Virus Life Cycle and Carcinogenesis 201
9.9. Conclusions 202
References 202
Human Papillomavirus E6 and E7 Oncogenes 211
10.1. Introduction 211
10.2. Papillomavirus E6 Proteins 211
10.3. Papillomavirus E7 Proteins 221
10.4. Role of the HPV E6 and E7 Genes in Survival and Proliferation of Cancer Cells 234
10.5. HPV E6 and E7 Proteins as Potential Therapeutic Targets 239
References 240
In Vivo Models for the Study of Animal and Human Papillomaviruses 267
11.1. Introduction 267
11.2. Animal Papillomaviruses 267
11.3. Transgenic Mouse Models for the Study of Human Papillomaviruses 271
11.4. Mechanistic Studies of E6 in Transgenic Mouse Models 274
11.5. Mechanistic Studies of E7 in Transgenic Mouse Models 275
11.6. Transgenic Mouse Studies on the Role of HPV in Cervical Cancer in Transgenic Mice 277
11.7. Use of HPV Transgenic Mice as Preclinical Models for Testing New Modalities for Preventing or Treating Cervical Cancer 279
11.8. Additional Mouse Models for HPV-Associated Neoplasia 280
11.9. Summary 281
References 282
The Humoral Immune Response to Human Papillomavirus 290
12.1. Introduction 290
12.2. Early Work on Identification of Humoral Immune Response 290
12.3. Serological Assays Using Proteins and Synthetic Peptides 291
12.4. VLPS/Capsomers 293
12.5. Capsid/Capsomer/VLP Production 293
12.6. Studies Defining HPV Virion Epitopes 303
12.7. Conclusions and Future Perspectives 306
References 307
Cell-Mediated Immune Responses to Human Papillomavirus 326
13.1. Introduction 326
13.2. Virally Induced Tumors 326
13.3. Immunology to Viral Assault 328
13.4. The Importance of Cell-Mediated Immunity 328
13.5. Immune Activation Against HPV Infection 330
13.6. Immune Evasion by HPV 331
13.7. The Importance of the CD4 Helper Response 336
13.8. Genetic Susceptibility to HPV Associated Carcinogenesis 337
13.9. Conclusions 338
References 339
Papillomavirus Vaccines 349
14.1. Introduction 349
14.2. Therapeutic Vaccines 349
14.3. Prophylactic Vaccines 359
References 373
Clinical Assessment, Therapies, New Tests, and Algorithms 382
15.1. Introduction 382
15.2. Human Papillomaviruses and Risk 382
15.3. HPV DNA Testing 385
15.4. Conventional Approaches to Pre-Invasive HPV- Related Diseases 391
15.5. New Therapeutic Approaches 392
15.6. Summary 393
References 394
Possible Worldwide Impact of Prevention of Human Papillomavirus Infection 398
16.1. Introduction 398
16.2. HPV Infection as a Cause of Cancer 401
16.3. Primary and Secondary Prevention Strategies 407
16.4. Conclusion 417
References 417
INDEX 425