The Papillomaviruses

by Garcea, Robert L.; Dimaio, Daniel

• ISBN13: 9780387365220
• ISBN10: 0387365222
• Edition: 1st
• Format: Hardcover
• Copyright: 2007-02-09
• Publisher: Springer Verlag

Summary

This volume will evaluate the carcinogenic risk to humans posed by infection with human papillomaviruses (HPVs). To date, more than 70 HPV types have been identified, of which over 15 have been reported in cervical cancer biopsies. Worldwide, cervical cancer is the second most common cancer in women; approximately 500,000+ new cases are diagnosed each year. Although investigations of cervical cancer are most abundant, the report also considers the possible involvement of HPV infection in cancers at other site of the human body. The rapid advances in papillomavirus biology and vaccine development have surpassed all current summaries of the field.

Table of Contents

Preface	p. v
List of Contributors	p. xvii
Principles of Human Tumor Virology	p. 1
Introduction	p. 1
Precedents in Animals	p. 1
Human Tumor Viruses	p. 2
Human Papillomaviruses	p. 3
Hepatitis Viruses	p. 3
Epstein-Barr Virus	p. 3
Human Herpesvirus-8	p. 4
Human T Lymphotropic Virus Type I	p. 4
SV40 as a Potential Human Tumor Virus	p. 4
Viral Tumors in the Developing World	p. 4
Mechanisms of Viral Tumorigenesis	p. 5
Immunity and Tumor Viruses	p. 6
Prospects for Prevention and Treatment	p. 7
Conclusions	p. 8
History of Papillomavirus Research	p. 13
Introduction	p. 13
The 1930s and 1940s: Biology of the Shope Papillomavirus and Other Animal Papillomaviruses	p. 14
The 1950s and 1960s: Cell Differentiation and Virus Replication	p. 16
The 1970s to the Early 1990s: Viral Genetics and the Emergence of HPV as a Medically Important Virus	p. 17
Phylogeny and Typing of Papillomaviruses	p. 29
Introduction	p. 29
Papillomaviridae: A Taxon Separate from the Polyomaviruses	p. 31
Novel Attempts to Improve the Nomenclature of Groups of Papillomavirus (PV) Types	p. 31
The Genus	p. 31
Papillomavirus "Species"	p. 33
Papillomavirus Types, the Natural Taxonomic Entities in Molecular and Clinical Investigations	p. 36
Papillomavirus Subtypes	p. 36
Papillomavirus Variants	p. 37
Papillomavirus Typing in Research and Clinical Practice	p. 38
General Considerations Regarding the Evolution of Papillomaviruses	p. 39
Evolution of Papillomaviruses: The Time Scale	p. 40
Pathogenicity Versus Latency	p. 41
The Differentiation-Dependent Life Cycle of Human Papillomaviruses in Keratinocytes	p. 45
Introduction	p. 45
Life Cycle of HPVs	p. 45
Methods to Study the HPV Life Cycle	p. 46
Genome Organization and Gene Products of HPVs	p. 49
Control of HPV Transcription	p. 52
Differentiation-Dependent Mechanisms to Regulate HPV DNA Replication	p. 54
Roles of the HPV E6 and E7 Proteins in the Viral Life Cycle	p. 55
Effects of HPVs on Epithelial Differentiation	p. 57
Conclusion	p. 58
Papillomavirus Structure and Assembly	p. 69
Introduction	p. 69
Structure Determination	p. 70
L1 Monomer	p. 72
Disulfide Bonds	p. 73
Pentamer-Pentamer Contacts	p. 74
Surface Loops and Epitopes	p. 76
L1 Self-Assembly	p. 77
Pseudovirion Synthesis	p. 79
Role of L2	p. 80
Nuclear Localization and DNA Binding of L1 and L2	p. 81
Summary	p. 83
Viral Entry and Receptors	p. 89
Introduction	p. 89
Binding to the Cell Surface	p. 91
Contribution of L2 to Viral Entry	p. 96
A Passage to Cytoplasm and Nucleus	p. 96
Conclusion	p. 101
Human Papillomavirus Transcription	p. 109
Introduction	p. 109
Papillomaviridae	p. 109
Papillomavirus Infections	p. 110
HPV Genome Organization	p. 110
Overview of Viral Transcription in Productive Infections	p. 112
Viral RNA Mapping in Warty Lesions	p. 113
Organotypic Raft Cultures of Primary Human Keratinocytes as a Model System to Study HPVs	p. 118
Viral RNAs in Organotypic Model Systems	p. 119
Where in the Stratified Squamous Epithelium Are E6 and E7 Proteins Expressed in Productively Infected Lesions?	p. 121
Mechanisms That Control the Expression of the E6 and E7 Proteins	p. 123
Transcriptional Regulation	p. 123
Post-Transcriptional Regulation	p. 124
What Is the Role of E2?	p. 125
Why Are There So Many Promoters and Spliced Transcripts?	p. 126
Basis For HPV Oncogenesis	p. 128
Transcription in Carcinomas and Cervical Carcinoma Cell Lines	p. 128
Are There Additional Viral Proteins Contributing to Viral Carcinogenesis?	p. 129
Concluding Remarks	p. 131
DNA Replication of Papillomaviruses	p. 145
Introduction	p. 145
Assays for Replication of Viral DNA	p. 146
Short-Term Replication Assays	p. 146
Viral DNA Replication In Vitro	p. 147
Is There More Than One Way to Replicate Viral DNA?	p. 147
Plasmid Maintenance	p. 148
The Relationship Between DNA Replication and Morphological Transformation	p. 148
The Basic Requirements for DNA Replication: E1, E2, and Ori	p. 149
The Requirement for Cellular Factors in Viral DNA Replication	p. 150
Description of the Parts	p. 151
The Viral Origin of DNA Replication	p. 151
Understanding the E1 Protein	p. 154
The E1 DBD	p. 154
Activities Associated with the E1 Protein	p. 157
The Interaction Between E1 and Cellular and Viral Factors Involved in DNA Replication	p. 160
Modifications of E1	p. 160
The Role of E2 in DNA Replication	p. 161
A Conflict Between Specific and Nonspecific DNA-Binding Activities in E1	p. 162
A Mechanism of Action for E2	p. 164
The E1-E2 Complex is a Precursor for Formation of Larger E1 Complexes	p. 164
The Viral DNA Replication Machinery as a Target for Small Molecule Intervention	p. 166
Papillomavirus E5 Proteins	p. 175
Introduction	p. 175
The BPV1 E5 Protein	p. 175
The Cellular Platelet-Derived Growth Factor [Beta]-Receptor as a Target of the BPV1 E5 Protein	p. 176
Model for the Transmembrane Interaction Between the BPV1 E5 Protein and the PDGF [Beta]-Receptor	p. 178
Selection and Analysis of Small Transmembrane Transforming Proteins Modeled on the BPV1 E5 Protein	p. 179
Alternative Models of BPV1 E5 Transformation	p. 179
The BPV4 E5 Protein	p. 180
The Human Papillomavirus E5 Proteins	p. 181
HPV16 E5 Protein and the EGF Receptor	p. 182
Interaction of E5 Proteins with the Vacuolar H[superscript +]-ATPase	p. 183
E5 Proteins and Major Histocompatibility Antigen Expression	p. 185
Effects of E5 Proteins on Apoptosis	p. 186
Role of E5 Proteins in the Virus Life Cycle and Carcinogenesis	p. 187
Conclusions	p. 188
Human Papillomavirus E6 and E7 Oncogenes	p. 197
Introduction	p. 197
Papillomavirus E6 Proteins	p. 197
Biochemical Characterization of Papillomavirus E6 Proteins	p. 198
Human Papillomavirus E6 Proteins	p. 199
Bovine Papillomavirus E6 Protein	p. 206
Papillomavirus E7 Proteins	p. 207
Biochemical Characterization of HPV E7 Proteins	p. 207
Biological Activities of the E7 Protein	p. 209
Association of E7 with the Retinoblastoma Tumor Suppressor pRB and the Related p107 and p130 Pocket Proteins	p. 210
Association of E7 with Histone-Modifying Enzymes	p. 212
Destabilization of pRB, p107, and p130	p. 213
HPV E7 and the p53 Tumor Suppressor	p. 214
Interactions of HPV E7 with Components of the Cell-Cycle Machinery	p. 215
Modulation of Cytostatic Cytokine Signaling by HPV E7	p. 216
Effects of HPV E7 on Cellular Metabolism	p. 218
HPV E7 and Chromosomal Instability	p. 218
Role of the HPV E6 and E7 Genes in Survival and Proliferation of Cancer Cells	p. 220
Antisense and Related Technologies That Reduce HPV RNA in Cervical Cancer Cells	p. 220
Small Molecules and Peptides That Inhibit HPV Expression or Activity in Cervical Carcinoma Cells	p. 221
Papillomavirus E2 Protein as a Repressor of HPV Expression in Cervical Carcinoma Cells	p. 222
HPV-Independent Effects of the E2 Protein	p. 224
HPV E6 and E7 Proteins as Potential Therapeutic Targets	p. 225
In Vivo Models for the Study of Animal and Human Papillomaviruses	p. 253
Introduction	p. 253
Animal Papillomaviruses	p. 253
Rabbit Papillomaviruses	p. 254
Bovine Papillomaviruses	p. 254
Other Animal Papillomavirus	p. 255
Use of Animal Papillomaviruses in the Analysis of Prophylactic Vaccines	p. 255
Transgenic Mouse Models for the Study of Human Papillomaviruses	p. 257
BPV Transgenic Mice	p. 258
HPV Transgenic Mice	p. 258
Mechanistic Studies of E6 in Transgenic Mouse Models	p. 260
Mechanistic Studies of E7 in Transgenic Mouse Models	p. 261
Transgenic Mouse Studies on the Role of HPV in Cervical Cancer in Transgenic Mice	p. 263
Use of HPV Transgenic Mice as Preclinical Models for Testing New Modalities for Preventing or Treating Cervical Cancer	p. 265
Additional Mouse Models for HPV-Associated Neoplasia	p. 266
Summary	p. 267
The Humoral Immune Response to Human Papillomavirus	p. 277
Introduction	p. 277
Early Work on Identification of Humoral Immune Response	p. 277
Serological Assays Using Proteins and Synthetic Peptides	p. 278
VLPs/Capsomers	p. 280
Introduction/Overview of Serological Methods	p. 280
Capsid/Capsomer/VLP Production	p. 280
Serological Assays	p. 281
Natural History and Serological Response to HPV Capsid Proteins	p. 284
Studies Defining HPV Virion Epitopes	p. 290
Details of Known L1 Epitopes	p. 290
Antibodies to the L2 Protein	p. 293
Conclusions and Future Perspectives	p. 293
Cell-Mediated Immune Responses to Human Papillomavirus	p. 313
Introduction	p. 313
Virally Induced Tumors	p. 313
Immunology to Viral Assault	p. 315
The Importance of Cell-Mediated Immunity	p. 315
Immune Activation Against HPV Infection	p. 317
Immune Evasion by HPV	p. 318
MHC Regulation	p. 319
Modulation of Antigen Presentation	p. 320
Loss of T-Cell-Receptor [Zeta]-Chain Expression	p. 320
Subversion of HPV by Cytokines	p. 321
The Importance of the CD4 Helper Response	p. 323
Genetic Susceptibility to HPV Associated Carcinogenesis	p. 324
Conclusions	p. 325
Papillomavirus Vaccines	p. 337
Introduction	p. 337
Therapeutic Vaccines	p. 337
Introduction	p. 337
Lessons from Natural History Studies	p. 341
Animal Models for Therapeutic HPV Vaccines	p. 341
Therapeutic Clinical Trials	p. 343
Type Specificity	p. 345
Why Haven't Therapeutic HPV Vaccines Been More Successful?	p. 346
Conclusions: Therapeutic Vaccines	p. 347
Prophylactic Vaccines	p. 347
Introduction	p. 347
Preclinical Studies	p. 348
Clinical Trials	p. 349
Remaining Scientific Questions	p. 353
Target Populations	p. 354
Implementation Issues	p. 355
Second-Generation Vaccines	p. 357
Conclusions: Prophylactic Vaccines	p. 360
Clinical Assessment, Therapies, New Tests, and Algorithms	p. 371
Introduction	p. 371
Human Papillomaviruses and Risk	p. 371
HPV Infection Is the Principal Cause of Cervical Neoplasia	p. 371
HPV Infection Is Extremely Common in Sexually Active, Reproductive-Age Women	p. 372
There Is a Broad Gradient of Risk Imposed by Cancer-Associated (High-Risk) HPV Types, with HPV Type 16 Conferring the Greatest Risk; Low-Risk HPV Types May Confer Risk as Surrogate Markers of At-Risk Behavior	p. 372
A Woman Harboring a Persistent High-Risk HPV Type in Her Genital Tract Is at Risk for Developing a High-Grade Squamous Intraepithelial Lesion (HSIL)	p. 372
Women Infected by HIV Are at Increased Risk of CIN	p. 373
Sexual History of the Male Sexual Partner Influences the Risk of Cervical Neoplasia	p. 373
HPV DNA Testing	p. 374
Screening	p. 374
Application to the Management of Atypical Squamous Cells of Undetermined Significance	p. 375
Management of Patients with Atypical Glandular Cells	p. 376
Problem-Oriented HPV DNA Testing	p. 377
Potential Risks of HPV DNA Testing	p. 378
Type-Specific HPV DNA Testing	p. 380
Conventional Approaches to Pre-Invasive HPV-Related Diseases	p. 380
Cytology- and Pathology-Based Management	p. 380
New Therapeutic Approaches	p. 381
Aldara	p. 381
Immunotherapeutics	p. 381
Preventive Vaccines	p. 382
Summary	p. 382
Possible Worldwide Impact of Prevention of Human Papillomavirus Infection	p. 387
Introduction	p. 387
HPV Infections Worldwide and Related Human Diseases	p. 387
Genital HPV Infections and Clinical Outcomes	p. 388
Prevalence and Incidence of HPV Infections	p. 389
HPV Infection as a Cause of Cancer	p. 390
Cancer of the Cervix Uteri	p. 390
Other Ano-Genital Cancers	p. 393
How Much Cancer Globally Is Related to Infection with HPV?	p. 394
Primary and Secondary Prevention Strategies	p. 396
Primary Prevention Strategies	p. 396
Secondary Prevention Strategies	p. 401
Conclusion	p. 406
Index	p. 415
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