Retroviruses and Insights into Cancer (eBook)

Preface 6
Contents 8
Contributors 10
Chapter 1: Overview of Retrovirology 14
Introduction 14
Retrovirus Structure 15
Retrovirus Classification 16
Retrovirus Replication 18
Retrovirus Replication and Effects on the Host 24
Endogenous Viruses 25
Other Consequences of Integration 26
Factors Influencing Infection 28
Types of Oncogenic Viruses 30
Replication-Competent Viruses and Tumor Induction 30
Replication-Defective Viruses that Lack Oncogenes 31
Viruses Containing Oncogenes 32
Conclusions 36
References 36
Chapter 2: Mechanisms of Oncogenesis by Retroviruses 44
Introduction 45
ALV Activates Myc by Promoter Insertion 46
ALV Activates Myc by Insertions in the 3'UTR 48
Bic is the Precursor of miR-155, the First oncomiR 49
Other Oncogenic Viruses Up-regulate Expression of oncomiRs 54
Rapid-onset B-cell Lymphomas are Induced by ALVInfection of Embryos 55
The ALV Negative Regulator of Splicing (NRS) Element Impairs Expression of Downstream Proto-oncogenes 56
Common ALV Integration Sites Upstream of TERT 59
Conclusions 59
Comparisons with Non-Avian Systems 60
References 61
Chapter 3: Deregulation of Signal Transduction Pathways by Oncogenic Retroviruses 66
Introduction 66
Oncogenic Retroviruses and their Encoded or Activated Signal Transducing Molecules 67
Cytokine and Growth Factor-Induced Signal Transduction Pathways that Regulate Cell Growth, Differentiation, and Survival 67
Oncogenic Retroviruses That Encode Constitutively Activated Signal Transducing Molecules 71
Oncogenic Retroviruses that Activate Host Signal Transducing Molecules 73
Mechanisms of Oncogenic Retrovirus Deregulation of Signal Transduction Pathways 73
Activation of Signal Transduction Pathways by the Tyrosine Kinase of the Lymphoma-Inducing Abelson Murine Leukemia Virus 74
Activation of Signal Transduction Pathways by the Envelope-Tyrosine Kinase Fusion Protein of S13 Avian Erythroblastosis Virus 78
Activation of Signal Transduction Pathways by the Envelope Protein of the Erythroleukemia-Inducing Friend Spleen Focus-Forming 79
Activation of Signal Transduction Pathways by the Envelope Protein of the Jaagsiekte Sheep Retrovirus 90
Summary 94
References 95
Chapter 4: Genetics of Host Resistance to Retroviruses and Cancer 108
Introduction 108
Avian Sarcoma/Leukosis Virus (ASLV) 109
Jaagsiekte Sheep Retrovirus (JSRV) 113
Murine Leukemia Viruses (MLV) 114
Mouse Mammary Tumor Virus (MMTV) 118
Conclusions 123
References 124
Chapter 5: Endogenous Retroviruses and Cancer 132
Introduction 132
Endogenous Retroviruses Linked to Cancer 133
Avian Sarcoma and Leukosis Viruses 133
Murine Leukemia Viruses (MuLVs) 136
Mouse Mammary Tumor Viruses 146
Feline Leukemia Viruses 154
Ovine Betaretroviruses 155
Human Endogenous Retroviruses (HERVs) and Cancer 160
Summary and Conclusions 161
References 162
Chapter 6: Retroviruses and Insights into Cancer: Retroviral Regulatory/Accessory Genes and Cancer 176
Introduction 177
Human T-cell Leukemia Virus (HTLV) 177
Genome and Replication 177
The Role of HTLV Tax in Cellular Transformation and Pathogenesis 179
Tax is a Regulator of Viral and Cellular Transcription 180
Tax Promotes Cell Survival 181
Tax is Involved in Cell-cycle Deregulation 183
Tax Promotes Aneuploidy and Genetic Instability 186
Tax Modulates DNA Damage Repair Pathways 187
Down-regulation of Tax Provides Selective Advantage to ATL Cells 189
HTLV-1 Antisense Gene, Hbz 190
Human Endogenous Retroviruses (HERVs) 192
HERV Genome and Classification 192
Disease Association 193
Regulator of Expression Encoded by cORF (Rec) 194
Np9 195
Summary 195
References 196
Chapter 7: Cancers Induced by Piscine Retroviruses 203
Introduction 204
Retroviruses of Fish Isolated in Cell Culture and Endogenous Fish Retroviruses 205
Snakehead Retrovirus 205
Zebrafish Endogenous Retrovirus 206
Xiphophorus Retrovirus 206
Proliferative Diseases of Fish and their Associated Retroviruses 207
Putative Retroviruses of White Suckers, Angel Fish, and Hooknose Fish 207
Northern Pike and Muskellunge-associated Viruses 208
Plasmacytoid Leukemia of Chinook Salmon 209
Damselfish Neurofibromatosis 211
Salmon Swim-Bladder Sarcoma-Associated Retrovirus 212
Epsilonretroviruses 213
Walleye Epidermal Hyperplasia 213
Perch Epidermal Hyperplasia 215
Walleye Dermal Sarcoma (WDS) 216
Experimental Transmission Studies 217
Molecular Characterization of WDSV 219
Roles of the WDSV Accessory Proteins in Pathogenesis 220
Phylogeny of Fish Retroviruses 223
References 225
Chapter 8: The Immune Response to Oncogenic Retroviruses 231
Introduction 231
Murine Oncogenic Retroviruses 233
Introduction to Oncogenic Murine Retroviruses 233
Type-Specific Immune Responses to MuLV: The FMR Exogenous Versus AKR/Gross Endogenous Systems 233
AKR/Gross MuLV-Specific CTL: Virus/Tumor Escape Mechanisms 234
An Immunodominant CTL Epitope in the p15E Viral Envelope Protein 234
Relevance of the KSPWFTTL Immunodominant CTL Epitope 235
Retroviral Variation within the Immunodominant CTL Epitope and Type Specificity 236
Retroviral Variation Outside the Epitope but Affecting the Immunodominant CTL Epitope 237
Retroviral Variation within Subdominant CTL Epitopes 238
A “Fail-Safe” Peripheral Tolerance Mechanism by AKR/Gross MuLV: Deregulated FasL Expression by Virus-Infected Cells Mediating the Elimination of Anti-Viral Effector T cells 239
Lack of Veto Cell Function by Other Immune Cell Subsets 242
The Pathogenesis of LP-BM5 MuLV-Induced Murine AIDS (MAIDS): Immune Suppression and Tumor Induction Versus “antiviral” CTL of Unique Specificities 244
Introduction to LP-BM5-Induced MAIDS and Tumor-Specific CTLs 244
CTL to a Uniquely Derived Gag Epitope of the BM5-helper and BM5-defective Retroviruses 245
Anti-ORF2 Gag/SYNTGRFPPL-specific CTL are Protective 246
Friend Murine Leukemia Virus Complex 248
Genetic Resistance to Infection: Genes Influencing Susceptibility to Immunosuppression and Leukemia 249
The Role of CD4+, CD8+, and B Cells During Acute and Chronic Stages of FV Infection 251
FV Immunomodulation: Viral Strategies to Evade Host Immune Responsiveness 254
Vaccination Studies: Protection Against FV-induced Disease 255
Vaccine Studies Utilizing FV-tumor Expressed Epitopes 256
Human Oncogenic Retroviruses 257
HTLV-I 257
Introduction to HTLV-1-Induced Diseases 257
HTLV-1 Pathogenesis: Virus-induced Alteration of Host Immunity 257
CD8+ CTL Response During Following HTLV-1: Do CTL Play a Role in Pathogenesis or Immunity During ATL? 258
Therapeutic Strategies for HTLV-1 Infection 259
References 262
Chapter 9: Retrovirus-induced Immunodeficiency and Cancer 271
AIDS-Related Malignancies 272
AIDS-Associated Kaposi’s Sarcoma (AIDS-KS) 273
AIDS-associated Non-Hodgkin’s Lymphoma (AIDS-NHL) 274
AIDS-associated Invasive Cervical Cancer (AIDS-ICC) 276
Increased Incidence of Non-AIDS-Defining Cancers (NADC) 277
The Role of HIV Infection in the Induction of AIDS-related Cancers 279
Evidence for an Indirect Role of HIV in the Induction of Cancer 279
Evidence for a Direct Role for HIV in the Induction of Cancer 282
Fidelity and Utility of a Nonhuman Primate Model for AIDS-NHL 284
Incidence and Epidemiologic Features of SAIDS-NHL 286
Morphologic Spectrum of SAIDS-NHL 287
Cell Type of Origin, Clonality and Pathologic Hallmarks of SAIDS-NHL 288
Viral Coinfections in SAIDS-NHL 289
Rhesus Lymphocryptovirus (RhLCV) 289
Rhesus Rhadinovirus (RRV) 290
Role of SIV in the Induction SAIDS-NHL 292
Summary and Future Directions 293
References 293
Chapter 10: Retroviruses as Tools to Identify Oncogenes and Tumor Suppressor Genes 296
Introduction 296
Basic Principles and Examples of Insertional Mutagenesis 298
Role of the Viral Enhancer in Disease Specificity 298
Oncogene Activation 300
Inactivation of Tumor-Suppressor Genes 301
Micro-RNAs as Targets for Retroviral Activation 301
Development of Cloning Methods for Retroviral Integration Sites 301
Advanced Applications of Retroviral Tagging 304
Theoretical Issues in Cancer Gene Discovery by Retroviral Tagging 306
Randomness of Integration and the Risk of False Attribution of CISs 306
Complex Loci: Identifying the Target Gene 307
Oncogene Complementation Groups: Functional Redundancy or Tumor Heterogeneity? 309
Prospects 309
Insertional Mutagenesis and Gene Therapy Safety 309
New technology and applications 311
References 311
Chapter 11: Emerging Retroviruses and Cancer 317
Introduction 318
Primate Gammaretroviruses: Initial Isolation and Associated Pathology 318
GALV and WMV Transmission in vivo and in vitro 322
Discovery of the Phosphate Transporter, SLC20A1 (PiT1), as the Receptor for GALV and WMV 324
Overview of Koala Retrovirus: Origins and Pathology 326
KoRV is an Endogenous Virus Highly Related to Gibbon Ape Leukemia Virus 329
The in vitro and in vivo Host Range of KoRV 330
KoRV Endogenization 331
Where Did GALV and KoRV Come from? 333
Cross-species Transmission 335
GALV in the Context of Emerging Infections 337
Concluding Comments 338
References 339
Index 344