Contents -- Foreword -- Preface -- Contributors -- Hepatitis B Virus -- Chapter 1 Natural Course of Chronic Hepatitis B Virus Infection Chia-Ming Chu and Yun-Fan Liaw -- Introduction -- Epidemiology of Chronic HBV Infection -- Clinical Presentation -- Phases of Chronic HBV Infection -- Immune Tolerant Phase -- Immune Clearance Phase -- Hepatitis Activity and Acute Hepatitis Flares (HBeAg-positive Chronic Hepatitis) during Immune Clearance Phase -- HBeAg to anti-HBe Seroconversion -- HBeAg Persistence and Its Outcome -- Inactive/Residual Phase -- Spontaneous HBsAg Seroclearance -- Reactivation of Hepatitis B -- HBeAg Reversion -- HBeAg-Negative Chronic Hepatitis -- Concurrent Viral Superinfection as Part of Natural Course -- Hepatitic C Virus -- Hepatitis D Virus -- Human Immunodeficiency Virus -- Sequelae and Mortality -- Cirrhosis and Contributing Factors -- Hepatic Decompensation and Mortality -- HCC and Contributing Factors -- Survival of Cirrhosis -- Conclusion -- References -- Chapter 2 Immune Response and Viral Hepatitis B David R. Milich -- Introduction -- Serology of Acute and Chronic HBV Infections -- The PreS Envelope Antigens -- Increased Complexity of the Serology of Chronic HBV Infection -- Human T Cell Responses in Acute and Chronic HBV Infection -- CD4 + Th Cell Response -- CD8 + CTL Response -- Innate Immunity to HBV -- Mechanisms of Liver Injury and Clearance -- Transgenic Models of Immune-mediated Liver Injury -- HBV Persistence -- Tolerogenicity of HBc/HBeAgs -- Immune Escape Variants -- Manifestations of HBV-Specific T Cell Tolerance -- Immunogenetics -- Summary -- Acknowledgment -- References -- Chapter 3 Epidemiology of Viral Hepatitis B-related Hepatocellular Carcinoma Katherine A. McGlynn, Alison A. Evans and W. Thomas London -- Introduction -- History -- Global Prevalence of Chronic HBV Infection.

Liver Cancer Incidence, Mortality, and Survival -- Demographic Factors -- Age -- Sex -- Ethnicity -- Risk Factors -- Aflatoxin -- Alcohol -- Tobacco -- Pesticides -- Iron-related Conditions -- Endogenous and Exogenous Hormones -- Host Susceptibility -- Susceptibility to Chronic HBV Infection -- Susceptibility to HCC Once Chronic HBV Infection is Established -- Viral Factors -- Viral Load -- Viral Genotype -- Viral Mutations -- HBV and Other Cancers -- Future Directions and Unresolved Issues -- References -- Chapter 4 Molecular Biology of HBV-related Hepatocellular Carcinoma Amanda J. Hodgson and Betty L. Slagle -- Abstract -- Introduction -- Lessons from Other Tumor Viruses -- HBV and HCC -- A Model for HBV-associated HCC -- Immune-mediated Pathogenesis -- Early Immune Response to HBV Infection -- Immune-mediated Clearance of HBV -- Immune Pathogenesis During Chronic Infection -- Effect of HBx on Liver Regeneration -- Liver Regeneration in HBV Transgenic Mice -- Role of Viral Integration in HCC -- General Features of HBV Integration -- Lessons Learned from the WHV System -- HBV Integration in Human HCCs -- Potential Oncogenic Properties of HBV Gene Products -- PreS1 -- PreS2 Truncations -- Regulatory HBx Protein -- HBx and the Cell Cycle -- Activation of Signal Transduction Pathways -- HBx and Apoptosis -- HBx and DNA Repair -- HBx and Genome Instability -- Does HBx Cause HCC in Transgenic Mice? -- HBV-associated HCC: Other Mechanisms -- MicroRNAs and HCC -- Tumor-specific DNA Loss in HCC -- Epigenetic Silencing by Promoter Hypermethylation -- Cooperation With Other Risk factors -- Prevention of HBV-related HCC -- Summary -- References -- Chapter 5 Treatment of Chronic Viral Hepatitis B and Drug Resistant Variants Tin Nguyen, Paul Desmond and Stephen Locarnini -- Abstract -- Introduction -- Selection of Drug Resistant Mutants -- Viral Factors.

Host Factors -- Antiviral Drug -- Mechanism of Action of Oral Antivirals Agents in Chronic HBV -- Pharmacokinetics of Oral Antiviral Agents in Chronic HBV -- Hepatocytes -- Molecular Basis of Antiviral Drug Resistance -- Primary and Secondary Mutations -- Pathways of Antiviral Drug Resistance -- L-nucleoside Pathway -- Acyclic Phosphonate Pathway -- Shared Pathway -- Naive Entecavir Resistance Pathway -- Therapy for Chronic HBV in Treatment-naive Patients -- Goals of Treatment for Chronic HBV Infection -- Indications for Treatment Initiation -- Combination Therapy -- Monitoring and Diagnosis of Antiviral Drug Resistance -- HBV Viral Load Assays -- Genotypic Resistance Testing -- The rtA181T / sW172* Mutant -- Management of Antiviral Resistance -- Resistance to L-nucleoside -- Acyclic Monophosphate Resistance -- Entecavir Resistance -- Clinical Consequences of Antiviral Drug Resistance -- Prevention of Antiviral Resistance -- Conclusion -- References -- Chapter 6 Virion Secretion of Naturally Occurring Core Antigen Variants of Human Hepatitis B Virus Chiaho Shih -- Introduction -- Highly Frequent Naturally Occurring HBV Core Variants -- HBV Core Mutations Associated with Liver Damage -- HBV Core Mutations Associated with Hepatoma Patients -- Immunoevasion of Naturally Occurring HBV Variants -- Immature Virion Secretion -- Deficiency in Viral DNA Replication of ayw Mutant F97L -- The Dogma of Genome Maturation Signal for Virion Secretion -- Immature Virion Secretion of ayw Mutant F97L -- Dissociation of Extracellular Immature Secretion from Intracellular DNA Replication in adr Mutant I97L -- Kinetic Studies of Immature Virion Secretion -- A Low-Level Virion Secretion Phenotype of Core Mutants P5T and L60V -- Naturally Occurring and Engineered Compensatory Mutations -- Compensatory Mutation of HBc P130T for Immature Virion Secretion.

Compensatory Mutation of HBc P5T for Immature Virion Secretion -- Engineered Compensatory Mutation pre-S1-A119F for Immature Virion Secretion -- Compensatory Envelope Mutation W74L for the Low Virion Secretion of Envelope Mutant L77R -- Host Factors and ESCRT Involved in Virion Secretion -- Replication Advantage and Host Factor Independent Phenotype of Mutant I97L -- Signal Transduction Via a Critical Hydrophobic Pocket Around Amino Acid 97 of HBc? -- Conclusions and Considerations -- Acknowledgments -- References -- Chapter 7 Recent Developments in Hepatitis Delta Virus Camille Sureau -- Introduction -- HDV Assembly -- HDV Entry -- preS1 Lipopeptides are Inhibitors of HDV/HBV Entry -- Role of Glycosaminoglycans in HDV Entry? -- Role of the "a" Determinant in HDV/HBV Entry -- HDV/HBV Entry Through the Endocytic Pathway? -- Replication of HDV RNA -- Cellular RNA Polymerase II is Involved in HDV RNA Transcription -- Syntheses of Genomic and Antigenomic HDV RNAs Occur in Different Nuclear Compartments -- HDV RNA Replication is Controlled by HDAg Post-Translational Modifications -- In Vitro Transcription of HDV RNA by Cellular RNA Polymerase II -- A Mechanism for Initiation of HDV RNA Transcription by Pol II -- HDV Ribozymes -- An HDV-like Ribozyme Encoded by the Human Genome -- Export of Genomic HDV RNA from the Nucleus -- The HDAg Proteins -- The Functions of the HDAg Proteins -- Conclusions -- Acknowledgments -- References -- Hepatitis C Virus -- Chapter 8 Development of an HCV Cell Culture System Takanobu Kato and Takaji Wakita -- Introduction -- Isolation of the JFH-1 Strain -- Subgenomic Replicon System with JFH-1 -- Establishment of JFH-1 Infection and the Replication System -- Robust HCV Infection Using Permissive Cell Lines -- HCV Infection and Replication System for Other Genotypes -- Applications of HCV Cell Culture System -- Conclusions.

Acknowledgments -- References -- Chapter 9 Regulation of Innate Immunity and Interferon Defenses by Hepatitis C Virus Stacy M. Horner and Michael Gale Jr -- Introduction -- Hepatocytes Detect HCV Infection Through RIG-I -- Actions of PRRs -- HCV is Recognized as Non-Self by RIG-I -- Molecular Mechanism of RIG-I Activation -- IFN Signaling During HCV Infection -- Control of Innate Immune Signaling by HCV -- HCV Disruption of IFN- β Induction -- Regulation of the RIG-I Pathway -- HCV Regulation of IFN Signaling and Antiviral Activities of IFN-Induced Proteins -- Conclusion and considerations -- Summary -- Acknowledgments -- References -- Chapter 10 Expression and Functions of Hepatitis C Virus F Protein Kamile Yuksek and Jing-hsiung James Ou -- Introduction -- The Discovery of the HCV F Protein -- Expression of the F Protein During Natural Infection -- Molecular Mechanisms for the Expression of the HCV F Protein -- Expression by Programmed Ribosomal Frameshift -- Expression of the F Protein by Translation Initiation from Internal AUG Codons -- Expression of the F Protein from a Non-AUG Codon -- Biological Functions of the F Protein -- Interaction between the F Protein and the Proteasome -- Regulation of Expression of Cytokines by the F Protein -- Possible Role of the F Protein in Hepatocellular Carcinogenesis -- HCV F Protein and Microtubules -- Conclusion -- References -- Chapter 11 Lymphotropism of Hepatitis C Virus Keigo Machida and Michael M.C. Lai -- 1. Introduction -- 2. Review of Evidence for Extrahepatic Infection of HCV -- 2.1. Epidemiological Evidence for the HCV Infection of B and T Cells in Hepatitis C Patients -- 2.2. Epidemiological Association Between HCV Infection and Lymphoma -- 2.3. Evidence Negating the Association between HCV Infection and Lymphoma.

2.4. Evidence for the Causal Association Between HCV Infection and B Cell Lymphoma: Interferon Treatment Induces the Regression of HCV-Positive Lymphoma.