Viruses and Human Cancer: From Basic Science to Clinical Prevention

Contents
1 An Introduction to Virus Infections and Human Cancer
1 The Burden of Virus-Induced Cancers
2 The Human Cancers Caused by Viruses
3 The Diversity of Human Oncoviruses
4 Oncogenic Mechanisms
4.1 Viral Infection and Cancer: Establishing Causality
4.2 The Importance of Identifying the Viral Etiology for a Cancer
4.3 The Search for Additional Oncoviruses
5 Conclusions
References
2 Epidemiology of Virus Infection and Human Cancer
1 Introduction
2 Transmission Routes and Infection Prevalence of Oncogenic Viruses in the World
3 Global Variation in the Incidence of Virus-Caused Cancers
4 Carcinogenic Mechanisms of Oncogenic Viruses
5 Lifetime Cumulative Incidence of Virus-Caused Cancers
6 Viral, Host, and Environmental Predictors of Virus-Caused Cancers
7 Risk Calculators of Virus-Caused Cancers
8 Prevention and Early Detection of Virus-Caused Cancers
9 Future Perspectives
References
3 Mechanisms of Hepatitis B Virus-Induced Hepatocarcinogenesis
1 Introduction to Hepatitis B Virus
1.1 HBV Genome and Lifecycle
1.2 HBV Genotypes and Clinical Outcomes of Chronic Hepatitis B
1.3 Spliced HBV RNA Variants and HBV Pathogenesis
1.4 HBV Viral Load and HCC
2 Genetic and Epigenetic Modifications Induced by HBV
2.1 HBV DNA Integration in Host Chromosomes
2.2 Epigenetic Modifications
2.2.1 DNA Methylation
2.2.2 Histone Modifications
2.3 MicroRNAs in HBV-Induced Hepatocarcinogenesis
2.4 Genetic Variations in HBV DNA
3 Role of HBx in HCC
3.1 HBx and Gene Expression
3.2 HBx and Cell Signaling
3.3 HBx and DNA Repair
3.4 HBx Mutants
4 Conclusions and Future Perspective
References
4 Prevention of Hepatitis B Virus Infection and Liver Cancer
1 Introduction
2 Disease Burden of HCC
3 Transmission Routes of Hepatitis B Virus Infection
4 Chronic Hepatitis B Virus Infection and Liver Cancer
4.1 Viral (HBV) Risk Factors for HCC
4.2 Host Factors for HCC (Table 1)
4.3 Maternal Effect
4.4 Environmental/Life Style Factors
5 Strategies of Liver Cancer Prevention
6 Primary Prevention of Hepatitis B Virus Infection by Immunization
6.1 Universal Hepatitis B Vaccination in Infancy
6.2 Effect of HBV Vaccination on the Reduction of HBV Infection and Related Complications
6.3 Effect of Liver Cancer Prevention by Immunization Against Hepatitis B Virus Infection (Table 3)
7 Secondary and Tertiary Prevention of Hepatitis B Related HCC
8 Problems to Be Solved in Liver Cancer Prevention
8.1 Low Coverage Rate of Universal Infant HBV Vaccination
8.2 Poor Compliance Caused by Anxiety to the Adverse Effects of Vaccination or Ignorance
8.3 Breakthrough Infection or Non-responsiveness in Vacinees
8.4 Problems of Secondary Prevention Using Current Antiviral Therapy
9 Strategies Toward a Successful Control of HBV-Related HCC
9.1 Prevention of Breakthrough HBV Infection
9.2 Screening High-Risk Subjects and Provide Secondary Prevention of HCC
10 Implication in Other Cancer Prevention and Future Prospects
Acknowledgements
References
5 The Oncogenic Role of Hepatitis C Virus
1 Introduction
2 Hepatitis C Virus and Viral Proteins
3 Possible Role of HCV in Hepatocarcinogenesis
4 In Vivo Oncogenic Activity of HCV Core Protein in Mice
5 Induction of Oxidative Stress via Mitochondria by HCV
6 Effect of HCV on Iron Metabolism
7 Induction of Hepatic Steatosis and Insulin Resistance by HCV
8 Interaction of HCV Core Protein with Host Proteins
9 Conclusion
References
6 Prevention of Hepatitis C Virus Infection and Liver Cancer
1 Introduction
2 Hepatitis C Infection
3 Hepatitis C Virology
4 Hepatitis C and Associated Risk Factors for HCC Development
4.1 Hepatitis C Viral Hepatocarcinogenesis
5 Prevention of HCC in Patients with Hepatitis C-Induced Cirrhosis
6 Prevention of Cirrhosis and HCC in Patients with Hepatitis C-Induced Chronic Hepatitis
7 Antiviral Treatment of Hepatitis C
7.1 Pegylated Interferon Alfa and Ribavirin
7.2 Direct-Acting Antiviral Agents
8 Zepatier® (Elbasvir 50 mg + Grazoprevir 100 mg, Merck & Co.)
9 Epclusa® (Sofosbuvir 400 mg + Velpatasvir 100 mg, Gilead Sciences)
10 Vosevi® (Sofosbuvir 400 mg + Velpatasvir 100 mg + Voxilaprevir 100 mg, Gilead Sciences)
11 Maviret® (Glecaprevir 100 mg + Pibrentasvir 40 mg, AbbVie)
12 Risk of HCC Development with DAA Therapy
13 Risk of Hepatitis B Reactivation and Flare with DAA Therapy
14 Prevention of the Acquisition of HCV in High-Risk Patients
14.1 Preventative Vaccines
14.2 Recombinant Adenoviral and MVA Vaccines for HCV
14.3 Recombinant Protein-Based Vaccines for HCV
14.4 Recombinant Virus-like Particle (VLP) Based Vaccines for HCV
14.5 Public Health Measures
15 Conclusions
References
7 High-Risk Human Papillomaviruses and DNA Repair
1 Introduction
2 Genome Organization
3 Viral Oncoproteins
4 The DNA Damage Response
5 The DNA Damage Response and HPV
6 Summary
Acknowledgements
References
8 Vaccination Strategies for the Control and Treatment of HPV Infection and HPV-Associated Cancer
1 Introduction
2 Current Preventive HPV Vaccines
3 Improving Preventive HPV Vaccine Development
4 Strategies for Therapeutic HPV Vaccine Development
4.1 Introduction to Therapeutic HPV Vaccines
4.2 Live Vector-Based Therapeutic HPV Vaccines
4.2.1 Bacterial Vectors
4.2.2 Viral Vectors
4.3 Peptide-Based Therapeutic HPV Vaccines
4.4 Protein-Based Vaccines
4.5 Dendritic Cell-Based Vaccines
4.6 DNA-Based Vaccines
4.7 Combination Strategies
5 Conclusion
Acknowledgements
References
9 Epstein–Barr Virus-Associated Post-transplant Lymphoproliferative Disease
1 Introduction
2 EBV, Cancer, and Aspects of EBV Biology
3 PTLD
4 Risk Factors
5 Virus Monitoring
6 Treatment
7 Prevention
References
10 HTLV-1 Replication and Adult T Cell Leukemia Development
1 Introduction
2 HTLV-1 Infection and Replication
2.1 Epidemiology of HTLV-1 Infection
2.2 Diagnosis of HTLV-1 Infection
2.3 HTLV-1 Tropism
2.4 HTLV-1 Genome Organization, Gene Expression, and Regulation
2.5 Models for Studying HTLV-1 Infection
2.5.1 HTLV-1 Infection in Cell Culture
2.5.2 HTLV-1 Infection in Humanized Immune-Deficient Mice
2.5.3 HTLV-1 Infection in Rabbits
2.6 Clonality of HTLV-1-Infected T Cells
2.6.1 HTLV-1 Clonality and Clone Abundance in Natural Infection
2.7 Clonal Abundance of HTLV-1-Infected Cells in Cell Culture and Humanized Mouse Models
3 HTLV-1 Tax
3.1 Tax Is a Potent Activator of HTLV-1 Transcription/Replication
3.2 Tax Hijacks Ubiquitin E3 Ligase RING Finger Protein 8 (RNF8) for Canonical IKK-NF-κB Activation
3.3 Aberrant Activation of RNF8 by Tax
3.4 Tax Promotes the Assembly of K63/M1-Linked Hybrid Polyubiquitin Chains
3.5 Tax-Mediated Activation of NIK and IKK1
3.6 The Biological Consequences of Tax-Mediated NF-κB Activation
3.6.1 Cell Transformation
3.6.2 Functional Inactivation of P53
3.6.3 Apoptosis Induction and Inhibition
3.6.4 Senescence Induction
3.7 Tax Expression and Outcomes of HTLV-1 Infection
4 HTLV-1 HBZ
4.1 HTLV-1 HBZ: Gene Expression and Viral Persistence
4.2 HBZ Promotes T Cell Proliferation
5 HTLV-1 and ATL
5.1 Tax and HBZ in Cellular Transformation and Tumorigenesis
5.2 Genomic Instability in ATL
5.2.1 Overview
5.2.2 Recurrent Mutations in ATL
5.3 Loss of Tax Expression and Acquisition of Tax-Independent NF-κB Activation in ATL Cells
5.4 ATL Cells Evolve Adaptive Changes to Accommodate Constitutive NF-κB Activation
5.5 Epigenetic Changes in ATL Cells
5.5.1 Aberrant DNA Methylation
5.5.2 Aberrant Histone Modifications
6 Concluding Remarks
Disclosure of Conflicts of Interest
References
11 Novel Functions and Virus–Host Interactions Implicated in Pathogenesis and Replication of Human Herpesvirus 8
1 Introduction
2 HHV-8 Latency Products and Autocrine Activities
2.1 Latency-Associated Nuclear Antigen (LANA)
2.2 Viral FLICE-Inhibitory Protein (vFLIP)
2.3 Kaposins
2.4 Viral Cyclin (v-Cyclin)
2.5 Viral Interleukin-6 (vIL-6) in PEL
2.6 Viral Interferon Regulatory Factor-3 (vIRF-3) in PEL
2.7 MicroRNAs (miRNAs)
3 Novel Virus–Host Interactions via Lytic Activities
3.1 Viral Interleukin-6 (vIL-6)
3.2 Viral CC-Chemokine Ligands (vCCLs)
3.3 Viral G Protein-Coupled Receptor (vGPCR)
3.4 Viral Interferon Regulatory Factors (vIRFs)
3.5 Viral BCL-2 (vBcl-2)
3.6 K7-Encoded Viral Inhibitor of Apoptosis (vIAP)
4 Terminal Membrane Proteins
4.1 K1/Variable ITAM-Containing Protein (VIP)
4.2 K15-Encoded Membrane Protein
5 Summary
References
12 Merkel Cell Polyomavirus and Human Merkel Cell Carcinoma
1 Introduction
2 The Life Cycle of MCPyV
2.1 MCPyV Genome Structure
2.2 MCPyV Entry into Host Cells
2.3 MCPyV Replication
2.4 Assembly and Release
2.5 MCPyV Host Cellular Tropism
2.6 MCPyV Species Tropism
3 The MCPyV Tumorigenic Mechanisms
4 Therapeutic Strategy Targeting MCPyV Infection
5 Human Merkel Cell Carcinoma
5.1 MCC Histopathologic Features
5.2 Origin of MCC
5.3 MCPyV-Positive and -Negative MCCs
6 Current Therapeutic Strategies for MCC
6.1 Surgery and Radiation Therapy
6.2 Immunotherapy
6.2.1 Immune Checkpoint Inhibitor Therapy
6.2.2 Adoptive Cell Transfer Therapy
6.3 DNA Cancer Vaccine
6.4 Targeted Therapies
7 Remaining Questions and Future Perspectives
References
13 Chapter XX Antiviral Treatment and Cancer Control
1 Introduction
2 Hepatitis B Virus and Hepatitis C Virus
2.1 Anti-HBV Therapies
2.2 Anti-HCV Therapies
3 HBV-HCV Coinfection
4 HBV-HIV Coinfection and HCV-HIV Coinfection
5 Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)
6 Human T-Cell Lymphotropic Virus Type 1 (HTLV-1)
7 Epstein-Barr Virus (EBV)
8 Human Papillomavirus (HPV)
9 Merkel Cell Polyomavirus (MCV)
10 Conclusion and Future Perspective
References