The Papillomaviruses-pdf-带标签

许璐

HPV方面的经典著作！现在还在读，呵呵。

原来是没有标签的，自己做了一个，中间还出了点问题，总共花了几个小时时间，晕



这家伙目录都长到吓人。。。可是为了以后看着方便还是咬咬牙做了。。。

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
1. Principles of Human Tumor Virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
George Klein and Daniel DiMaio
1.1. Introduction ...................................................................................... 1
1.2. Precedents in Animals...................................................................... 1
1.3. Human Tumor Viruses..................................................................... 2
1.3.1. Human Papillomaviruses ..................................................... 3
1.3.2. Hepatitis Viruses .................................................................. 3
1.3.3. Epstein–Barr Virus............................................................... 3
1.3.4. Human Herpesvirus-8 .......................................................... 4
1.3.5. Human T Lymphotropic Virus Type I ................................ 4
1.3.6. SV40 as a Potential Human Tumor Virus .......................... 4
1.3.7. Viral Tumors in the Developing World .............................. 4
1.4. Mechanisms of Viral Tumorigenesis............................................... 5
1.5. Immunity and Tumor Viruses.......................................................... 6
1.6. Prospects for Prevention and Treatment.......................................... 7
1.7. Conclusions ...................................................................................... 8
2. History of Papillomavirus Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Douglas R. Lowy
2.1. Introduction ...................................................................................... 13
2.2. The 1930s and 1940s: Biology of the Shope Papillomavirus
and Other Animal Papillomaviruses ................................................ 14
2.3. The 1950s and 1960s: Cell Differentiation
and Virus Replication....................................................................... 16
2.4. The 1970s to the Early 1990s: Viral Genetics
and the Emergence of HPV as a Medically
Important Virus ................................................................................ 17
vii
viii Contents
3. Phylogeny and Typing of Papillomaviruses. . . . . . . . . . . . . . . . . . . . . . . . 29
Hans-Ulrich Bernard
3.1. Introduction ...................................................................................... 29
3.2. Papillomaviridae: A Taxon Separate from the Polyomaviruses ..... 31
3.3. Novel Attempts to Improve the Nomenclature of Groups
of Papillomavirus (PV) Types ......................................................... 31
3.3.1. The Genus ............................................................................ 31
3.3.2. Papillomavirus “Species”..................................................... 33
3.4. Papillomavirus Types, the Natural Taxonomic Entities
in Molecular and Clinical Investigations......................................... 36
3.5. Papillomavirus Subtypes .................................................................. 36
3.6. Papillomavirus Variants ................................................................... 37
3.7. Papillomavirus Typing in Research and Clinical Practice.............. 38
3.8. General Considerations Regarding the Evolution
of Papillomaviruses .......................................................................... 39
3.9. Evolution of Papillomaviruses: The Time Scale............................. 40
3.10. Pathogenicity Versus Latency.......................................................... 41
4. The Differentiation-Dependent Life Cycle of Human
Papillomaviruses in Keratinocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Choogho Lee and Laimonis A. Laimins
4.1. Introduction ...................................................................................... 45
4.2. Life Cycle of HPVs ......................................................................... 45
4.3. Methods to Study the HPV Life Cycle ........................................... 46
4.4. Genome Organization and Gene Products of HPVs ....................... 49
4.5. Control of HPV Transcription ......................................................... 52
4.6. Differentiation-Dependent Mechanisms to Regulate HPV
DNA Replication .............................................................................. 54
4.7. Roles of the HPV E6 and E7 Proteins in the Viral Life Cycle...... 55
4.8. Effects of HPVs on Epithelial Differentiation ................................ 57
4.9. Conclusion........................................................................................ 58
5. Papillomavirus Structure and Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Robert L. Garcea and Xiaojiang Chen
5.1. Introduction ...................................................................................... 69
5.2. Structure Determination ................................................................... 70
5.3. L1 Monomer..................................................................................... 72
5.4. Disulfide Bonds................................................................................ 73
5.5. Pentamer–Pentamer Contacts........................................................... 74
5.6. Surface Loops and Epitopes ............................................................ 76
5.7. L1 Self-Assembly............................................................................. 77
5.8. Pseudovirion Synthesis .................................................................... 79
5.9. Role of L2 ........................................................................................ 80
Contents ix
5.10. Nuclear Localization and DNA Binding of L1 and L2 .................. 81
5.11. Summary........................................................................................... 83
6. Viral Entry and Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Rolf E. Streeck, Hans-Christoph Selinka, and Martin Sapp
6.1. Introduction ...................................................................................... 89
6.2. Binding to the Cell Surface ............................................................. 91
6.3. Contribution of L2 to Viral Entry ................................................... 96
6.4. A Passage to Cytoplasm and Nucleus ............................................. 96
6.5. Conclusion........................................................................................ 101
7. Human Papillomavirus Transcription . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109
Louise T. Chow and Thomas R. Broker
7.1. Introduction ...................................................................................... 109
7.1.1. Papillomaviridae................................................................... 109
7.1.2. Papillomavirus Infections .................................................... 110
7.1.3. HPV Genome Organization ................................................. 110
7.2. Overview of Viral Transcription in Productive Infections ............. 112
7.3. Viral RNA Mapping in Warty Lesions ........................................... 113
7.4. Organotypic Raft Cultures of Primary Human Keratinocytes
as a Model System to Study HPVs..................................................118
7.4.1. Viral RNAs in Organotypic Model Systems....................... 119
7.5. Where in the Stratified Squamous Epithelium Are E6 and E7
Proteins Expressed in Productively Infected Lesions?....................121
7.6. Mechanisms That Control the Expression
of the E6 and E7 Proteins ................................................................123
7.6.1. Transcriptional Regulation................................................... 123
7.6.2. Post-Transcriptional Regulation .......................................... 124
7.7. What Is the Role of E2? .................................................................. 125
7.8. Why Are There So Many Promoters and Spliced Transcripts?...... 126
7.9. Basis For HPV Oncogenesis............................................................ 128
7.9.1. Transcription in Carcinomas and Cervical Carcinoma
Cell Lines .............................................................................128
7.9.2. Are There Additional Viral Proteins Contributing
to Viral Carcinogenesis? ......................................................129
7.10. Concluding Remarks........................................................................ 131
8. DNA Replication of Papillomaviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Arne Stenlund
8.1. Introduction ...................................................................................... 145
8.2. Assays for Replication of Viral DNA ............................................. 146
8.2.1. Short-Term Replication Assays ........................................... 146
8.2.2. Viral DNA Replication In Vitro.......................................... 147
x Contents
8.2.3. Is There More Than One Way to Replicate
Viral DNA? ..........................................................................147
8.3. Plasmid Maintenance ....................................................................... 148
8.4. The Relationship Between DNA Replication
and Morphological Transformation .................................................148
8.5. The Basic Requirements for DNA Replication:
E1, E2, and Ori.................................................................................149
8.6. The Requirement for Cellular Factors in Viral
DNA Replication ..............................................................................150
8.7. Description of the Parts ................................................................... 151
8.7.1. The Viral Origin of DNA Replication ................................ 151
8.8. Understanding the E1 Protein .......................................................... 154
8.8.1. The E1 DBD ........................................................................ 154
8.8.2. Activities Associated with the E1 Protein........................... 157
8.9. The Interaction Between E1 and Cellular and Viral Factors
Involved in DNA Replication ..........................................................160
8.9.1. Modifications of E1 ............................................................. 160
8.9.2. The Role of E2 in DNA Replication................................... 161
8.10. A Conflict Between Specific and Nonspecific DNA-Binding
Activities in E1.................................................................................162
8.11. A Mechanism of Action for E2....................................................... 164
8.12. The E1-E2 Complex is a Precursor for Formation of Larger
E1 Complexes...................................................................................164
8.13. The Viral DNA Replication Machinery as a Target
for Small Molecule Intervention ......................................................166
9. Papillomavirus E5 Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .175
Daniel DiMaio
9.1. Introduction ...................................................................................... 175
9.2. The BPV1 E5 Protein ...................................................................... 175
9.2.1. The Cellular Platelet-Derived Growth Factor
-Receptor as a Target of the BPV1 E5 Protein.................176
9.2.2. Model for the Transmembrane Interaction Between
the BPV1 E5 Protein and the PDGF -Receptor................178
9.2.3. Selection and Analysis of Small Transmembrane
Transforming Proteins Modeled on the BPV1
E5 Protein.............................................................................179
9.2.4. Alternative Models of BPV1 E5 Transformation ............... 179
9.3. The BPV4 E5 Protein ...................................................................... 180
9.4. The Human Papillomavirus E5 Proteins ......................................... 181
9.4.1. HPV16 E5 Protein and the EGF Receptor.......................... 182
9.5. Interaction of E5 Proteins with the Vacuolar H+-ATPase ............. 183
9.6. E5 Proteins and Major Histocompatibility Antigen Expression..... 185
9.7. Effects of E5 Proteins on Apoptosis ............................................... 186
Contents xi
9.8. Role of E5 Proteins in the Virus Life Cycle
and Carcinogenesis...........................................................................187
9.9. Conclusions ...................................................................................... 188
10. Human Papillomavirus E6 and E7 Oncogenes. . . . . . . . . . . . . . . . . . . . .197
Karl Münger, Peter Howley, and Daniel DiMaio
10.1. Introduction ...................................................................................... 197
10.2. Papillomavirus E6 Proteins.............................................................. 197
10.2.1. Biochemical Characterization of Papillomavirus
E6 Proteins .........................................................................198
10.2.2. Human Papillomavirus E6 Proteins................................... 199
10.2.3. Bovine Papillomavirus E6 Protein .................................... 206
10.3. Papillomavirus E7 Proteins.............................................................. 207
10.3.1. Biochemical Characterization of HPV E7 Proteins .......... 207
10.3.2. Biological Activities of the E7 Protein ............................. 209
10.3.3. Association of E7 with the Retinoblastoma Tumor
Suppressor pRB and the Related p107 and p130
Pocket Proteins...................................................................210
10.3.4. Association of E7 with Histone-Modifying Enzymes ...... 212
10.3.5. Destabilization of pRB, p107, and p130 ........................... 213
10.3.6. HPV E7 and the p53 Tumor Suppressor........................... 214
10.3.7. Interactions of HPV E7 with Components
of the Cell-Cycle Machinery .............................................215
10.3.8. Modulation of Cytostatic Cytokine Signaling
by HPV E7 .........................................................................216
10.3.9. Effects of HPV E7 on Cellular Metabolism ..................... 218
10.3.10. HPV E7 and Chromosomal Instability.............................. 218
10.4. Role of the HPV E6 and E7 Genes in Survival
and Proliferation of Cancer Cells ....................................................220
10.4.1. Antisense and Related Technologies That Reduce
HPV RNA in Cervical Cancer Cells .................................220
10.4.2. Small Molecules and Peptides That Inhibit HPV
Expression or Activity in Cervical Carcinoma Cells ........221
10.4.3. Papillomavirus E2 Protein as a Repressor of HPV
Expression in Cervical Carcinoma Cells ...........................222
10.4.4. HPV-Independent Effects of the E2 Protein ..................... 224
10.5. HPV E6 and E7 Proteins as Potential Therapeutic Targets............ 225
11. In Vivo Models for the Study of Animal and Human
Papillomaviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Paul F. Lambert and Anne E. Griep
11.1. Introduction ...................................................................................... 253
11.2. Animal Papillomaviruses ................................................................. 253
xii Contents
11.2.1. Rabbit Papillomaviruses .................................................... 254
11.2.2. Bovine Papillomaviruses.................................................... 254
11.2.3. Other Animal Papillomavirus ............................................ 255
11.2.4. Use of Animal Papillomaviruses in the Analysis
of Prophylactic Vaccines ...................................................255
11.3. Transgenic Mouse Models for the Study of Human
Papillomaviruses...............................................................................257
11.3.1. BPV Transgenic Mice........................................................ 258
11.3.2. HPV Transgenic Mice ....................................................... 258
11.4. Mechanistic Studies of E6 in Transgenic Mouse Models............... 260
11.5. Mechanistic Studies of E7 in Transgenic Mouse Models............... 261
11.6. Transgenic Mouse Studies on the Role of HPV in Cervical
Cancer in Transgenic Mice ..............................................................263
11.7. Use of HPV Transgenic Mice as Preclinical Models
for Testing New Modalities for Preventing or Treating
Cervical Cancer ................................................................................265
11.8. Additional Mouse Models for HPV-Associated Neoplasia ............ 266
11.9. Summary........................................................................................... 267
12. The Humoral Immune Response to Human
Papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .277
Erin M. Egelkrout and Denise A. Galloway
12.1. Introduction ...................................................................................... 277
12.2. Early Work on Identification of Humoral Immune
Response...........................................................................................277
12.3. Serological Assays Using Proteins and Synthetic Peptides ............ 278
12.4. VLPs/Capsomers .............................................................................. 280
12.4.1. Introduction/Overview of Serological Methods................ 280
12.5. Capsid/Capsomer/VLP Production .................................................. 280
12.5.1. Serological Assays ............................................................. 281
12.5.2. Natural History and Serological Response to HPV
Capsid Proteins...................................................................284
12.6. Studies Defining HPV Virion Epitopes........................................... 290
12.6.1. Details of Known L1 Epitopes .......................................... 290
12.6.2. Antibodies to the L2 Protein ............................................. 293
12.7. Conclusions and Future Perspectives .............................................. 293
13. Cell-Mediated Immune Responses to Human
Papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .313
Gretchen Eiben Lyons, Michael I. Nishimura, and W. Martin Kast
13.1. Introduction ...................................................................................... 313
13.2. Virally Induced Tumors................................................................... 313
13.3. Immunology to Viral Assault .......................................................... 315
Contents xiii
13.4. The Importance of Cell-Mediated Immunity .................................. 315
13.5. Immune Activation Against HPV Infection .................................... 317
13.6. Immune Evasion by HPV................................................................ 318
13.6.1. MHC Regulation ................................................................ 319
13.6.2. Modulation of Antigen Presentation.................................. 320
13.6.3. Loss of T-Cell-Receptor -Chain Expression ................... 320
13.6.4. Subversion of HPV by Cytokines ..................................... 321
13.7. The Importance of the CD4 Helper Response ................................ 323
13.8. Genetic Susceptibility to HPV Associated Carcinogenesis ............ 324
13.9. Conclusions ...................................................................................... 325
14. Papillomavirus Vaccines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .337
John Schiller
14.1. Introduction ...................................................................................... 337
14.2. Therapeutic Vaccines ....................................................................... 337
14.2.1. Introduction ........................................................................ 337
14.2.2. Lessons from Natural History Studies............................... 341
14.2.3. Animal Models for Therapeutic HPV Vaccines ............... 341
14.2.4. Therapeutic Clinical Trials ................................................ 343
14.2.5. Type Specificity ................................................................. 345
14.2.6. Why Haven’t Therapeutic HPV Vaccines
Been More Successful?......................................................346
14.2.7. Conclusions: Therapeutic Vaccines................................... 347
14.3. Prophylactic Vaccines ...................................................................... 347
14.3.1. Introduction ........................................................................ 347
14.3.2. Preclinical Studies.............................................................. 348
14.3.3. Clinical Trials..................................................................... 349
14.3.4. Remaining Scientific Questions......................................... 353
14.3.5. Target Populations ............................................................. 354
14.3.6. Implementation Issues........................................................ 355
14.3.7. Second-Generation Vaccines ............................................. 357
14.3.8. Conclusions: Prophylactic Vaccines.................................. 360
15. Clinical Assessment, Therapies, New Tests,
and Algorithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Christopher P. Crum, and Ralph M. Richart
15.1. Introduction ...................................................................................... 371
15.2. Human Papillomaviruses and Risk.................................................. 371
15.2.1. HPV Infection Is the Principal Cause
of Cervical Neoplasia.........................................................371
15.2.2. HPV Infection Is Extremely Common in Sexually
Active, Reproductive-Age Women....................................372
xiv Contents
15.2.3. 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 .......................372
15.2.4. 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) ....................................................................372
15.2.5. Women Infected by HIV Are at Increased Risk
of CIN.................................................................................373
15.2.6. Sexual History of the Male Sexual Partner
Influences the Risk of Cervical Neoplasia ........................373
15.3. HPV DNA Testing ........................................................................... 374
15.3.1. Screening............................................................................ 374
15.3.2. Application to the Management of Atypical
Squamous Cells of Undetermined
Significance ........................................................................375
15.3.3. Management of Patients with Atypical
Glandular Cells...................................................................376
15.3.4. Problem-Oriented HPV DNA Testing............................... 377
15.3.5. Potential Risks of HPV DNA Testing............................... 378
15.3.6. Type-Specific HPV DNA Testing..................................... 380
15.4. Conventional Approaches to Pre-Invasive HPV-Related
Diseases ............................................................................................380
15.4.1. Cytology- and Pathology-Based Management.................. 380
15.5. New Therapeutic Approaches.......................................................... 381
15.5.1. Aldara ................................................................................. 381
15.5.2. Immunotherapeutics ........................................................... 381
15.5.3. Preventive Vaccines........................................................... 382
15.6. Summary........................................................................................... 382
16. Possible Worldwide Impact of Prevention of Human
Papillomavirus Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Sonia R. Pagliusi, M. Teresa Aguado,
and D. Maxwell Parkin
16.1. Introduction ...................................................................................... 387
16.1.1. HPV Infections Worldwide and Related
Human Diseases .................................................................387
16.1.2. Genital HPV Infections and Clinical Outcomes ............... 388
16.1.3. Prevalence and Incidence of HPV Infections ................... 389
16.2. HPV Infection as a Cause of Cancer............................................... 390
16.2.1. Cancer of the Cervix Uteri ................................................ 390
16.2.2. Other Ano-Genital Cancers ............................................... 393
Contents xv
16.2.3. How Much Cancer Globally Is Related
to Infection with HPV?......................................................394
16.3. Primary and Secondary Prevention Strategies ................................ 396
16.3.1. Primary Prevention Strategies ........................................... 396
16.3.2. Secondary Prevention Strategies ....................................... 401
16.4. Conclusion........................................................................................ 406
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415


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