Hepatitis E Virus

Preface to the Second Edition
Contents
Editor and Contributors
1: Hepatitis E Virus
	1.1 The Discovery of ET-NANBH
	1.2 Molecular Cloning of the ET-NANBH Virus Genome
	1.3 Classification of HEV
	1.4 Structure of the HEV Genome
	1.5 Morphological Appearance and Physiochemical Properties of ET-NANB
	1.6 Conclusions and Perspective
	References
2: Characteristics and Functions of HEV Proteins
	2.1 ORF1 Protein
		2.1.1 Structural Features of ORF1 Proteins
		2.1.2 Expression of ORF1
		2.1.3 Virus Infection and Pathogenicity Relevant to ORF1
		2.1.4 ORF1 and Virus Replication
		2.1.5 ORF1 and Viral Adaption
	2.2 ORF2 Protein
		2.2.1 Expression of HEV ORF2 Protein
		2.2.2 ORF2 Involved in HEV Infection and Intercellular Transduction
		2.2.3 ORF2 and the Endoplasmic Reticulum Stress Response (ERSR)
		2.2.4 ORF2 Interferes Host Innate Immunity
	2.3 ORF3 Protein
		2.3.1 Molecular Structure of ORF3 Protein
		2.3.2 ORF3 Protein and Host Cell Survival
		2.3.3 ORF3 Protein and the Virus Replication Environment
		2.3.4 ORF3 Protein and Clinical Symptoms
		2.3.5 ORF3 Protein Is Associated with HEV Release
	2.4 ORF4 Protein
		2.4.1 Features and Expression of ORF4
		2.4.2 ORF4 Protein and HEV Replication
	2.5 Conclusion
	References
3: Epidemiology of Hepatitis E
	3.1 Introduction
	3.2 Worldwide HEV Serological Prevalence in the Human Population
		3.2.1 Difference of HEV Serological Prevalence Between Countries
		3.2.2 Difference of HEV Serological Prevalence Between Regions Within a Country
		3.2.3 HEV Serological Prevalence Increases with Age in General Populations
		3.2.4 The Changing of HEV Seroprevalence over Time
	3.3 HEV Genotype Distribution Worldwide
		3.3.1 Asia
		3.3.2 Africa
		3.3.3 America
		3.3.4 Europe
		3.3.5 Australia and New Zealand
	3.4 Epidemiologic Patterns of HEV Infection
		3.4.1 The Epidemiologic Pattern of Infection with HEV-1 and HEV-2
			3.4.1.1 Reservoirs of HEV-1 and HEV-2
			3.4.1.2 Waterborne Outbreaks of Hepatitis E
			3.4.1.3 Sporadic Hepatitis E in Hyperendemic Regions
		3.4.2 Epidemiologic Pattern of HEV Infection in Industrialized Countries
		3.4.3 The Shifting Epidemiology Pattern of Hepatitis E in China
	3.5 Hepatitis E Prevention and Control
	3.6 Conclusion
	References
4: Hepatitis E as a Zoonosis
	4.1 Introduction to Zoonotic HEV Infections
	4.2 Introduction to HEV Infection in Animals
	4.3 Taxonomical Considerations
	4.4 Swine HEV
	4.5 Wild Boar HEV
	4.6 Rabbit HEV
	4.7 Avian HEV
	4.8 Camelid HEV
	4.9 Rat HEV
	4.10 Other Animal Species Infected by HEV
	4.11 Conclusions
	References
5: Genetic Evolution of Hepatitis E Virus
	5.1 General Variation
	5.2 ORF1 Variation
		5.2.1 Common HVR Properties Between Genotypes
		5.2.2 Divergence and Variation in the HVR from Various HEV Genotypes
		5.2.3 The Relationship Between HVR Variation and HVR Characteristics
	5.3 ORF2 Variation
		5.3.1 Epitope Analysis of ORF2 Protein
		5.3.2 Mutations in Potential Glycosylation Sites
		5.3.3 Mutations in the Capsid Protein
	5.4 ORF3 Protein
		5.4.1 Divergence of ORF3 Genes and Proteins from Various HEV Genotypes
		5.4.2 Immunogenicity and Antigenic Epitopes in the ORF3 Protein
	5.5 Conclusion
	References
6: Transmission of Hepatitis E Virus
	6.1 Introduction
	6.2 Waterborne Transmission of HEV
		6.2.1 Waterborne Transmission of HEV-1 and HEV-2
		6.2.2 Waterborne Transmission of HEV-3 and HEV-4
			6.2.2.1 Surface Water Contamination and Transmission of HEV
			6.2.2.2 Coastal Water Contamination and Transmission of HEV
	6.3 Zoonotic Risks and Foodborne Transmission
		6.3.1 Known and Potential Animal Reservoirs
		6.3.2 Zoonotic Transmission Through Direct Contact with Infected Animals
		6.3.3 Animal Derived Foodborne Transmission
	6.4 Blood-Borne Transmission of HEV
		6.4.1 Seroprevalence and Incidence of HEV Infection in Blood Donors
		6.4.2 Transfusion-Acquired Hepatitis E Cases
		6.4.3 The Consequences of Transfusion-Transmitted HEV Infection
		6.4.4 Hepatitis E Screening for Blood Donations
	6.5 HEV Transmission Through Organ Transplantation
	6.6 Vertical Transmission of HEV
		6.6.1 The Incidence of HEV Infection in Pregnant Women
		6.6.2 The Incidence of Vertical HEV Transmission
		6.6.3 The Outcome of HEV-Infected Babies
	6.7 Conclusion
	References
7: Immunobiology and Host Response to HEV
	7.1 Innate Immune Responses to HEV
		7.1.1 Induction of Apoptosis
		7.1.2 Innate Sensing by Toll-Like Receptors (TLRs)
		7.1.3 HEV Infection-Mediated IFNs
		7.1.4 Activation of NK Cells
		7.1.5 Alteration of NF-κB Activity
		7.1.6 Alteration of Other Factors in the Innate Immune Responses
	7.2 Specific Antibody Responses to HEV
		7.2.1 Major Antigenic Determinants
			7.2.1.1 Identification of the Immunodominant Region on HEV
			7.2.1.2 Critical Role of Correct Folding of the Immunodominant Region in Detecting Anti-HEV Antibodies
			7.2.1.3 Essential Role of Dimerization of the Immunodominant Region in Detecting Anti-HEV Antibodies
		7.2.2 Antibody Responses to Immunodominant Antigenic Determinants
			7.2.2.1 Anti-HEV IgM and IgG Responses in Experimentally Infected Animal Models
			7.2.2.2 Anti-HEV IgM and IgG Responses in Naturally Infected Humans
			7.2.2.3 Persistence of Anti-HEV IgG
			7.2.2.4 Anti-HEV IgA Response
			7.2.2.5 Cross-Reactivity and Cross-Protection of Anti-HEV Antibodies to Different Human HEV Genotypes
			7.2.2.6 Antibody Responses to Other Antigenic Determinants
			7.2.2.7 Rare Events in the Antibody Responses to HEV Infection
			7.2.2.8 Significance of Anti-HEV Responses
	7.3 Adaptive T-cell Immune Response to HEV
	7.4 Conclusion
	References
8: HEV Cell Culture
	8.1 Introduction
	8.2 HEV Cell Culture
		8.2.1 Overview of HEV Cell Culture
		8.2.2 Sources of Primary Virus Stocks
		8.2.3 Host Cells
		8.2.4 Impact of Medium Components on HEV Culture
	8.3 Genetic Mutation During HEV Passage
	8.4 HEV Infectious cDNA Clone
	8.5 Applications of Cell Culture
		8.5.1 Viral Thermal Stability Studies
		8.5.2 HEV Genome Structure and Function Analysis
		8.5.3 pORF1 Post-translational Processing and HVR Function Analysis
		8.5.4 pORF2 Post-translational Processing and Its Function in Virus Assembly and Determination of Host Range
		8.5.5 pORF3 Role in the Envelope Formation and Virus Release
		8.5.6 Neutralization Analysis
	8.6 Summary and Outlook
	References
9: Liver Organoid Potential Application for Hepatitis E Virus Infection
	9.1 Introduction
	9.2 Overview of HEV Life Cycle
	9.3 Organoid as a Model for HEV Infection
		9.3.1 What Are Organoids?
		9.3.2 Liver Organoid
		9.3.3 Liver Organoids Generation
		9.3.4 Liver Organoids for Hepatitis Virus Infections
		9.3.5 Liver Organoids Potentially for HEV Infection
	9.4 Conclusion and Outlook
	References
10: Hepatitis E Virus Life Cycle
	10.1 Introduction
	10.2 Attachment and Entry
		10.2.1 Entry of Naked HEV (neHEV)
		10.2.2 Entry of Quasi-Enveloped HEV (eHEV)
		10.2.3 Methods for Discovery of Functional HEV Receptor(s)
	10.3 Translation, Replication, and Transcription
		10.3.1 Translation
		10.3.2 Replication and Transcription
			10.3.2.1 ORF1: The Enzyme Catalyzes the Viral Genome Replication and Transcription
			10.3.2.2 Host Factors Regulate Virus Replication and Transcription
	10.4 Assembly and Release
		10.4.1 ORF2: Viral Capsid Protein
		10.4.2 ORF3: The Viroporin Regulating Viral Particles Release
	10.5 Summary
	References
11: Morphogenesis of Hepatitis E Virus
	11.1 The Morphology and Composition of Non-enveloped and Quasi-Enveloped Virions
		11.1.1 HEV Particles in Feces Are Non-enveloped
		11.1.2 HEV Particles Circulating in the Bloodstream and in Culture Fluid are Associated with Lipid Membrane
		11.1.3 The Protein and Lipid Composition in Non-enveloped and Quasi-Enveloped HEV
	11.2 The Formation of Naked and Quasi-Enveloped HEV Particles
	11.3 Attachment Factors and Receptors Hijacked by Non-enveloped and Quasi-Enveloped HEV
		11.3.1 Attachment Factors and Receptors Hijacked by Non-enveloped HEV
		11.3.2 Attachment Factors and Receptors Hijacked by Quasi-Enveloped HEV
	11.4 The Internalization and Uncoating of Non-enveloped and Quasi-Enveloped HEV
		11.4.1 The Internalization of Non-enveloped and Quasi-Enveloped HEV
		11.4.2 The Uncoating of Non-enveloped and Quasi-Enveloped HEV
	11.5 Potential Roles of Non-enveloped and Quasi-Enveloped HEV in Viral Transmission, Tropism, and Spread
		11.5.1 Transmission of Non-enveloped and Quasi-Enveloped HEV
		11.5.2 Potential Role of Quasi-Enveloped HEV in Viral Extrahepatic Replication
	11.6 Conclusions and Perspectives
	References
12: Animal Models for Hepatitis E Virus
	12.1 Introduction
	12.2 Nonhuman Primate Models
		12.2.1 Pathogenesis
		12.2.2 Cross-Species Infection
		12.2.3 Vaccine Studies
	12.3 Rabbit Models
		12.3.1 Pathogenesis
		12.3.2 Cross-Species Infection
		12.3.3 Vaccine Studies and Antiviral Screening
	12.4 Pig Models
		12.4.1 Pathogenesis
		12.4.2 Cross-Species Infection
		12.4.3 Vaccine Studies
	12.5 Chicken Models
		12.5.1 Pathogenesis
		12.5.2 Vaccine Study
	12.6 Mice with Humanized Liver
	12.7 Mongolian Gerbil Models
	12.8 Ferret Models
	12.9 Conclusion
	References
13: Clinical Manifestations of Hepatitis E
	13.1 Introduction
	13.2 Acute Hepatitis E
		13.2.1 Clinical Manifestations
		13.2.2 Pathology
		13.2.3 Diagnosis
	13.3 Chronic Hepatitis E
	13.4 Extrahepatic Complications of HEV Infection
		13.4.1 Neurological Complications
		13.4.2 Thrombocytopenia
		13.4.3 Hemolysis
	13.5 Other Complications Associated with HEV
		13.5.1 Acute Pancreatitis Associated with Hepatitis E
		13.5.2 Autoimmune Disorders Associated with HEV Infection
			13.5.2.1 Allergic Purpura
			13.5.2.2 Nephritis
			13.5.2.3 Aplastic Anemia
	13.6 Hepatitis E in Pregnant Women
		13.6.1 Clinical Features
		13.6.2 Treatment and Prevention
	13.7 HEV Infection in Neonates
	13.8 Special Manifestations
	13.9 Conclusion
	References
14: Laboratory Diagnosis of HEV Infection
	14.1 Dynamic Changes in HEV Markers After HEV Infection
	14.2 Clinical Diagnostic Criteria of HEV Infection
	14.3 Assays Used in Laboratory Diagnoses
		14.3.1 Antigens Used in Antibody Detecting Assays
		14.3.2 Anti-HEV IgG, IgM Assays
		14.3.3 Total HEV Antibody Assays
		14.3.4 HEV Antigen Assays
		14.3.5 HEV Nucleic Acids Detecting Assays
	14.4 Immunohistochemical Detection of HEV Proteins in Liver Tissue
	14.5 Conclusion and Prospective
	References
15: Treatment of Hepatitis E
	15.1 Acute Hepatitis E Treatment
	15.2 Chronic Hepatitis E Treatment
		15.2.1 Reduction of Immunosuppressive Medication
		15.2.2 Treatment with Ribavirin
		15.2.3 Treatment with Pegylated Interferon-α
		15.2.4 Treatment with Sofosbuvir
		15.2.5 Treatment of Extrahepatic Complications
	15.3 Treatment of HEV-Related Cholestatic Hepatitis
	15.4 Treatment of HEV-Related Liver Failure
		15.4.1 Clinical Assessment, Monitoring, and Standard Care
		15.4.2 Supportive Treatment
		15.4.3 Etiological Treatment
		15.4.4 Prevention and Treatment of Complications
		15.4.5 Liver Support Devices
		15.4.6 Liver Transplantation
	15.5 Evaluation of Antiviral Drugs In Vitro and in Animal Models
	15.6 Conclusion
	References
16: Prophylactic Hepatitis E Vaccine
	16.1 Introduction
	16.2 Rationale for Developing a Hepatitis E Vaccine
	16.3 Neutralizing Epitopes
	16.4 Assembly of Virus-Like Particle
	16.5 Hepatitis E Vaccine Candidates
		16.5.1 Trp-C2 Protein
		16.5.2 56 kDa Proteins
		16.5.3 HEV E2 Protein and HEV 239 VLP
	16.6 Clinical Trials
		16.6.1 56 kDa Vaccine
		16.6.2 HEV 239 Vaccine
	16.7 Critical Quality Attributes of HEV239 Vaccine
		16.7.1 Biochemical Methods
		16.7.2 Biophysical Methods
		16.7.3 Immunochemical Methods
		16.7.4 Immunological Assessment
	16.8 Target Populations
	References
17: Puzzles for Hepatitis E Virus
	17.1 Introduction
	17.2 Genome Organization of HEV
	17.3 Classification and Animal Hosts of HEV
	17.4 Transmission of HEV
	17.5 Chronic HEV Infection
	17.6 HEV-Associated Extra-Hepatic Manifestations
	17.7 Prevention of HEV Infection
	17.8 Treatment
		17.8.1 Treatment of Acute HEV Infection
		17.8.2 Treatment of Chronic HEV Infection
	17.9 Conclusion and Perspectives
	References