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1
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Zhang F, Xu LD, Wu S, Wang B, Xu P, Huang YW. Deciphering the hepatitis E virus ORF1: Functional domains, protein processing, and patient-derived mutations. Virology 2025; 603:110350. [PMID: 39675187 DOI: 10.1016/j.virol.2024.110350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/25/2024] [Accepted: 12/05/2024] [Indexed: 12/17/2024]
Abstract
Hepatitis E virus (HEV) is a major cause of acute and chronic hepatitis in humans. The HEV open reading frames (ORF1) encodes a large non-structural protein essential for viral replication, which contains several functional domains, including helicase and RNA-dependent RNA polymerase. A confusing aspect is that, while RNA viruses typically encode large polyproteins that rely on their enzymatic activity for processing into functional units, the processing of the ORF1 protein and the mechanisms involved remain unclear. The ORF1 plays a pivotal role in the viral life cycle, thus mutations in this region, especially those occurring under environmental pressures such as during antiviral drug treatment, could significantly affect viral replication and survival. Here, we summarize the recent advances in the functional domains, processing, and mutations of ORF1. Gaining a deeper understanding of HEV biology, particularly focusing on ORF1, could facilitate the development of new strategies to control HEV infections.
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Affiliation(s)
- Fei Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Ling-Dong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Laboratory Animal Center, Zhejiang University, Hangzhou, 310058, China
| | - Shiying Wu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, 310018, China
| | - Bin Wang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China
| | - Pinglong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China.
| | - Yao-Wei Huang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China.
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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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3
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Muñoz-Chimeno M, Rodriguez-Paredes V, García-Lugo MA, Avellon A. Hepatitis E genotype 3 genome: A comprehensive analysis of entropy, motif conservation, relevant mutations, and clade-associated polymorphisms. Front Microbiol 2022; 13:1011662. [PMID: 36274715 PMCID: PMC9582770 DOI: 10.3389/fmicb.2022.1011662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatitis E virus genotype 3 (HEV-3) is an EU/EEA emergent zoonosis. HEV-3 clades/subtypes have been described. Its genome contains ORF1, which encodes nonstructural proteins for virus replication, ORF2, the capsid protein, and ORF3, a multifunctional protein involved in virion pathogenesis. The study aims with respect to HEV-3 are to: (1) calculate genome entropy (excluding hypervariable region); (2) analyze the described motifs/mutations; (3) characterize clade/subtype genome polymorphisms. Seven hundred and five sequences from the GenBank database were used. The highest entropies were identified in zoonotic genotypes (HEV-3 and HEV-4) with respect to HEV-1 in X domain, RdRp, ORF2, and ORF3. There were statistically significant differences in the entropy between proteins, protease and ORF3 being the most variable and Y domain being the most conserved. Methyltransferase and Y domain motifs were completely conserved. By contrast, essential protease H581 residue and catalytic dyad exhibited amino acid changes in 1.8% and 0.4% of sequences, respectively. Several X domain amino acids were associated with clades. We found sequences with mutations in all helicase motifs except number IV. Helicase mutations related to increased virulence and/or fulminant hepatitis were frequent, the 1,110 residue being a typical HEV-3e and HEV-3f-A2 polymorphism. RdRp motifs III, V, VII also had high mutation rates. Motif III included residues that are polymorphisms of HEV-3e (F1449) and HEV-3 m (D1451). RdRp ribavirin resistance mutations were frequent, mainly 1479I (67.4, 100% in HEV-3efglmk) and 1634R/K (10.0%, almost 100% in HEV-3e). With respect to ORF2, 19/27 neutralization epitopes had mutations. The S80 residue in ORF3 presented mutations in 3.5% of cases. Amino acids in the ORF3-PSAP motif had high substitution rates, being more frequent in the first PSAP (44.8%) than in the second (1.5%). This is the first comprehensive analysis of the HEV-3 genome, aimed at improving our knowledge of the genome, and establishing the basis for future genotype-to-phenotype analysis, given that viral features associated with severity have not been explored in depth. Our results demonstrate there are important genetic differences in the studied genomes that sometimes affect significant viral structures, and constitute clade/subtype polymorphisms that may affect the clinical course or treatment efficacy.
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Affiliation(s)
- Milagros Muñoz-Chimeno
- Hepatitis Unit, National Center of Microbiology, Carlos III Institute of Health, Madrid, Spain
- Alcalá de Henares University, Madrid, Spain
| | | | | | - Ana Avellon
- Hepatitis Unit, National Center of Microbiology, Carlos III Institute of Health, Madrid, Spain
- CIBERESP Epidemiology and Public Health, Madrid, Spain
- *Correspondence: Ana Avellon,
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4
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Shata MTM, Hetta HF, Sharma Y, Sherman KE. Viral hepatitis in pregnancy. J Viral Hepat 2022; 29:844-861. [PMID: 35748741 PMCID: PMC9541692 DOI: 10.1111/jvh.13725] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/17/2021] [Accepted: 06/13/2022] [Indexed: 12/09/2022]
Abstract
Viral hepatitis is caused by a heterogenous group of viral agents representing a wide range of phylogenetic groups. Many viruses can involve the liver and cause liver injury but only a subset are delineated as 'hepatitis viruses' based upon their primary site of replication and tropism for hepatocytes which make up the bulk of the liver cell population. Since their discovery, beginning with the agent that caused serum hepatitis in the 1960s, the alphabetic designations have been utilized. To date, we have five hepatitis viruses, A through E, though it is postulated that others may exist. This chapter will focus on those viruses. Note that hepatitis D is included as a subset of hepatitis B, as it cannot exist without concurrent hepatitis B infection. Pregnancy has the potential to affect all aspects of these viral agents due to the unique immunologic and physiologic changes that occur during and after the gestational period. In this review, we will discuss the most common viral hepatitis and their effects during pregnancy.
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Affiliation(s)
- Mohamed Tarek M. Shata
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Helal F. Hetta
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA,Department of Medical Microbiology and Immunology, Faculty of MedicineAssiut UniversityAssiutEgypt
| | - Yeshika Sharma
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Kenneth E. Sherman
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
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5
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Cancela F, Noceti O, Arbiza J, Mirazo S. Structural aspects of hepatitis E virus. Arch Virol 2022; 167:2457-2481. [PMID: 36098802 PMCID: PMC9469829 DOI: 10.1007/s00705-022-05575-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/04/2022] [Indexed: 12/14/2022]
Abstract
Hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Hepatitis E is an enterically transmitted zoonotic disease that causes large waterborne epidemic outbreaks in developing countries and has become an increasing public-health concern in industrialized countries. In this setting, the infection is usually acute and self-limiting in immunocompetent individuals, although chronic cases in immunocompromised patients have been reported, frequently associated with several extrahepatic manifestations. Moreover, extrahepatic manifestations have also been reported in immunocompetent individuals with acute HEV infection. HEV belongs to the alphavirus-like supergroup III of single-stranded positive-sense RNA viruses, and its genome contains three partially overlapping open reading frames (ORFs). ORF1 encodes a nonstructural protein with eight domains, most of which have not been extensively characterized: methyltransferase, Y domain, papain-like cysteine protease, hypervariable region, proline-rich region, X domain, Hel domain, and RNA-dependent RNA polymerase. ORF2 and ORF3 encode the capsid protein and a multifunctional protein believed to be involved in virion release, respectively. The novel ORF4 is only expressed in HEV genotype 1 under endoplasmic reticulum stress conditions, and its exact function has not yet been elucidated. Despite important advances in recent years, the biological and molecular processes underlying HEV replication remain poorly understood, primarily due to a lack of detailed information about the functions of the viral proteins and the mechanisms involved in host-pathogen interactions. This review summarizes the current knowledge concerning HEV proteins and their biological properties, providing updated detailed data describing their function and focusing in detail on their structural characteristics. Furthermore, we review some unclear aspects of the four proteins encoded by the ORFs, highlighting the current key information gaps and discussing potential novel experimental strategies for shedding light on those issues.
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Affiliation(s)
- Florencia Cancela
- grid.11630.350000000121657640Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ofelia Noceti
- grid.414402.70000 0004 0469 0889Programa Nacional de Trasplante Hepático y Unidad Docente Asistencial Centro Nacional de Tratamiento Hepatobiliopancreatico. Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
| | - Juan Arbiza
- grid.11630.350000000121657640Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Santiago Mirazo
- grid.11630.350000000121657640Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay ,grid.11630.350000000121657640Departamento de Bacteriología y Virología, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay ,Av. Alfredo Navarro 3051, PC 11600 Montevideo, Uruguay
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6
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Mallet V, Scarano Pereira JP, Martinino A, Roque-Afonso AM. The rise of the hepatitis E virus. J Hepatol 2021; 75:1491-1493. [PMID: 34538615 DOI: 10.1016/j.jhep.2021.04.038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/04/2022]
Affiliation(s)
- Vincent Mallet
- AP-HP. Centre Université de Paris, Groupe Hospitalier Cochin Port Royal, DMU Cancérologie et spécialités médico-chirurgicales, Service d'Hépatologie, Paris, France.
| | - Juan-Pablo Scarano Pereira
- AP-HP. Centre Université de Paris, Groupe Hospitalier Cochin Port Royal, DMU Cancérologie et spécialités médico-chirurgicales, Service d'Hépatologie, Paris, France
| | - Alessandro Martinino
- AP-HP. Centre Université de Paris, Groupe Hospitalier Cochin Port Royal, DMU Cancérologie et spécialités médico-chirurgicales, Service d'Hépatologie, Paris, France
| | - Anne-Marie Roque-Afonso
- APHP. Université Paris-Saclay, Hôpital Paul Brousse, DMU Biologie - Génétique - PUI, Service de Virologie, Villejuif, France; Institut National de la Santé et de la Recherche Médicale unité 1193, Villejuif, France
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7
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Koyama M, Yamazaki T, Joshita S, Ito A, Ono K, Watanabe T, Yamashita Y, Sugiura A, Kobayashi M, Sato Y, Takahashi M, Okamoto H, Umemura T. An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection. Intern Med 2021; 60:1863-1870. [PMID: 33518570 PMCID: PMC8263169 DOI: 10.2169/internalmedicine.6337-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
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Affiliation(s)
- Mizuki Koyama
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Akihiro Ito
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Kazuyuki Ono
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Takayuki Watanabe
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
| | - Mikiko Kobayashi
- Department of Pathology, Shinshu University School of Medicine, Japan
| | - Yoshinori Sato
- Department of Pathology, Shinshu University School of Medicine, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan
- Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Japan
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Abstract
BACKGROUND Hepatitis E virus (HEV) generally causes self-limiting viral hepatitis. However, in pregnant women, HEV infection can be severe and has been associated with up to 30% mortality in the third trimester. Additionally, HEV infection in pregnancy is also associated with high rates of preterm labor and vertical transmission. MAIN BODY HEV is now recognized as a global health problem in both developing and industrialized countries. HEV can be transmitted via the fecal-oral route, zoonotic route, and blood transfusion route. An altered immune status, hormonal levels, and viral factors may be related to the severity of the disease. Currently, no established treatment is available for HEV in pregnant women. A Chinese vaccine has been demonstrated to be protective against HEV in the general population and seems to be safe in pregnancy; however, its safety and efficacy in a large population of pregnant women remain to be determined. CONCLUSION This review summarizes the current knowledge about HEV infection during pregnancy and focuses on the epidemiology, clinical manifestations, mechanisms underlying severe liver injury, and management and prevention of HEV infection during pregnancy. Considering that HEV infection during pregnancy may result in poor outcomes, screening for and monitoring HEV infection early in pregnancy should be taken into account. In addition, a better understanding of the pathogenesis will help to develop potential treatment strategies targeting HEV infection in pregnancy.
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Affiliation(s)
- Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Xiaoxue Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Jianbo Xia
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China.
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9
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Hartard C, Gantzer C, Bronowicki JP, Schvoerer E. Emerging hepatitis E virus compared with hepatitis A virus: A new sanitary challenge. Rev Med Virol 2019; 29:e2078. [PMID: 31456241 DOI: 10.1002/rmv.2078] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022]
Abstract
Hepatitis A (HAV) and E (HEV) viruses are able to cause liver disease in humans. Among the five classical hepatotropic viruses, they are mainly transmitted via the fecal-oral route. Historically, many similarities have thus been described between them according to their incidence and their pathogenicity, especially in countries with poor sanitary conditions. However, recent advances have provided new insights, and the gap is widening between them. Indeed, while HAV infection incidence tends to decrease in developed countries along with public health improvement, HEV is currently considered as an underdiagnosed emerging pathogen. HEV autochthonous infections are increasingly observed and are mainly associated with zoonotic transmissions. Extra hepatic signs resulting in neurological or renal impairments have also been reported for HEV, as well as a chronic carrier state in immunocompromised patients, arguing in favor of differential pathogenesis between those two viruses. Recent molecular tools have allowed studies of viral genome variability and investigation of links between viral plasticity and clinical evolution. The identification of key functional mutations in viral genomes may improve the knowledge of their clinical impact and is analyzed in depth in the present review.
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Affiliation(s)
- Cédric Hartard
- Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France.,Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Christophe Gantzer
- Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | | | - Evelyne Schvoerer
- Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France.,Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), UMR 7564, Vandoeuvre-lès-Nancy, France.,CNRS, LCPME UMR 7564, Nancy, France.,Faculté des Sciences et Technologies, Institut Jean Barriol, Université de Lorraine, Vandœuvre-lès-Nancy, France
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Primadharsini PP, Nagashima S, Okamoto H. Genetic Variability and Evolution of Hepatitis E Virus. Viruses 2019; 11:E456. [PMID: 31109076 PMCID: PMC6563261 DOI: 10.3390/v11050456] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/15/2019] [Accepted: 05/16/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatitis E virus (HEV) is a single-stranded positive-sense RNA virus. HEV can cause both acute and chronic hepatitis, with the latter usually occurring in immunocompromised patients. Modes of transmission range from the classic fecal-oral route or zoonotic route, to relatively recently recognized but increasingly common routes, such as via the transfusion of blood products or organ transplantation. Extrahepatic manifestations, such as neurological, kidney and hematological abnormalities, have been documented in some limited cases, typically in patients with immune suppression. HEV has demonstrated extensive genomic diversity and a variety of HEV strains have been identified worldwide from human populations as well as growing numbers of animal species. The genetic variability and constant evolution of HEV contribute to its physiopathogenesis and adaptation to new hosts. This review describes the recent classification of the Hepeviridae family, global genotype distribution, clinical significance of HEV genotype and genomic variability and evolution of HEV.
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Affiliation(s)
- Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan.
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan.
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan.
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11
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Narayanan S, Abutaleb A, Sherman KE, Kottilil S. Clinical features and determinants of chronicity in hepatitis E virus infection. J Viral Hepat 2019; 26:414-421. [PMID: 30636092 PMCID: PMC6437685 DOI: 10.1111/jvh.13059] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 10/25/2018] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus (HEV) has traditionally been associated with an acute, self-limiting hepatitis and is not known to have any chronic sequelae. HEV genotypes 1 and 2, which are human pathogens, have been associated with this self-limiting presentation, in both sporadic and epidemic settings. HEV genotype 3, which is zoonotically transmitted, is increasingly being reported as a cause of chronic infection in immunocompromised patients. These include patients with solid organ transplants, patients receiving chemotherapy for haematologic malignancies and patients infected with HIV. Chronic infection is associated with rapidly progressing liver disease and extrahepatic manifestations including neurologic disorders. We review the clinical manifestations of chronic HEV infection and discuss factors determining persistence and chronicity of HEV.
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Affiliation(s)
- Shivakumar Narayanan
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland
| | - Ameer Abutaleb
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland,Division of Gastroenterology & Hepatology, University of Maryland, Baltimore, Maryland
| | - Kenneth E. Sherman
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland
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12
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Haffar S, Shalimar, Kaur RJ, Wang Z, Prokop LJ, Murad MH, Bazerbachi F. Acute liver failure caused by hepatitis E virus genotype 3 and 4: A systematic review and pooled analysis. Liver Int 2018; 38:1965-1973. [PMID: 29675889 DOI: 10.1111/liv.13861] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 04/03/2018] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Acute liver failure caused by hepatitis E virus genotype 3 and 4 has been rarely described. Because of the presence of a short golden therapeutic window in patients with viral acute liver failure from other causes, it is possible that early recognition and treatment might reduce the morbidity and mortality. We performed a systematic review and pooled analysis of acute liver failure caused by hepatitis E virus genotype 3 and 4. METHODS Two reviewers appraised studies after searching multiple databases on June 12th, 2017. Appropriate tests were used to compare hepatitis E virus genotype 3 vs 4, suspected vs confirmed genotypes, hepatitis E virus-RNA positive vs negative, and to discern important mortality risk factors. RESULTS We identified 65 patients, with median age 58 years (range: 3-79), and a male to female ratio of 1.2:1. The median bilirubin, ALT, AST and alkaline phosphatase (expressed by multiplication of the upper limit of normal) levels were 14.8, 45.3, 34.8 and 1.63 respectively. Antihepatitis E virus IgG, antihepatitis E virus IgM and hepatitis E virus-RNA were positive in 84%, 91% and 86% of patients respectively. The median interval from symptoms onset to acute liver failure was 23 days, and 16 patients underwent liver transplantation. Final outcome was reported in 58 patients and mortality was 46%. Age was a predictor of poor prognosis in multivariate analysis. No important differences were found between patients infected with genotype 3 vs 4, patients with confirmed vs suspected genotypes, or patients with positive vs negative RNA. CONCLUSION Acute liver failure caused by hepatitis E virus genotype 3 and 4 is rare, similar between genotypes, occurs commonly in middle-aged/elderly patients and has a very high mortality. Age is predictive of poor prognosis in multivariate analysis.
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Affiliation(s)
- Samir Haffar
- Digestive center for diagnosis and treatment, Damascus, Syrian Arab Republic
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Ravinder J Kaur
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Zhen Wang
- Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Larry J Prokop
- Library Public Services, Mayo Clinic, Rochester, MN, USA
| | - Mohammad H Murad
- Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Fateh Bazerbachi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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13
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Todt D, Meister TL, Steinmann E. Hepatitis E virus treatment and ribavirin therapy: viral mechanisms of nonresponse. Curr Opin Virol 2018; 32:80-87. [PMID: 30384328 DOI: 10.1016/j.coviro.2018.10.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/27/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) can cause chronic infections in immunosuppressed patients with adverse clinical outcomes. Intervention strategies are limited with ribavirin (RBV) being the only main therapeutic option as off-label drug. Recent reports on RBV monotherapy failures show a coherence with the presence of certain single nucleotide variants (SNVs) and in-frame insertions in the hypervariable region of open reading frame 1 in the HEV genome. Importantly, some of the alterations were present in the viral population as minor variant before RBV administration. Individualized infection medicine by early detection of emerging viral variants in patients could improve treatment outcome and prognosis.
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Affiliation(s)
- Daniel Todt
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
| | - Toni Luise Meister
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
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14
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Smith DB, Simmonds P. Classification and Genomic Diversity of Enterically Transmitted Hepatitis Viruses. Cold Spring Harb Perspect Med 2018; 8:a031880. [PMID: 29530950 PMCID: PMC6120691 DOI: 10.1101/cshperspect.a031880] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatitis A virus (HAV) and hepatitis E virus (HEV) are significant human pathogens and are responsible for a substantial proportion of cases of severe acute hepatitis worldwide. Genetically, both viruses are heterogeneous and are classified into several genotypes that differ in their geographical distribution and risk group association. There is, however, little evidence that variants of HAV or HEV differ antigenically or in their propensity to cause severe disease. Genetically more divergent but primarily hepatotropic variants of both HAV and HEV have been found in several mammalian species, those of HAV being classified into eight species within the genus Hepatovirus in the virus family Picornaviridae. HEV is classified as a member of the species Orthohepevirus A in the virus family Hepeviridae, a species that additionally contains viruses infecting pigs, rabbits, and a variety of other mammalian species. Other species (Orthohepevirus B-D) infect a wide range of other mammalian species including rodents and bats.
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Affiliation(s)
- Donald B Smith
- Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom
| | - Peter Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom
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15
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Substitution of amino acid residue V1213 in the helicase domain of the genotype 3 hepatitis E virus reduces virus replication. Virol J 2018; 15:32. [PMID: 29422085 PMCID: PMC5806379 DOI: 10.1186/s12985-018-0943-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 02/01/2018] [Indexed: 12/17/2022] Open
Abstract
Background Genotype 3 hepatitis E virus (HEV) infection is generally associated with mild disease. However, recently eight genotype 3 HEV isolates were identified from patients with severe hepatitis. Importantly, three mutations (S605P, I978V and V1213A) in these genotype 3 isolates were found to be typical of genotype 4 HEV, which is sometime associated with more severe hepatitis. Therefore in this study we seek to determine if these unique mutations contribute to enhanced virus replication and thus potentially severe disease. Methods In the lack of an efficient cell culture system to study the effect of mutations on HEV replication, we developed a genotype 3 HEV replicon with Renilla luciferase (Rluc) as reporter and subsequently used it to construct numerous mutants, including swMu-1 (V1213A), swMu-2 (Q1246H), swMu-3 (V1213A and Q1246H), swMu-4 (S605P and I978V), and swMu-5 (V1213A, S605P and I978V). RNA transcripts from mutant replicons were transfected into Huh7 S10–3 liver cells to measure the effect of mutations on HEV replication efficiency. Results The results showed that the V1213A mutant had the highest reduction in HEV replication efficiency than other mutants. The V1213A and S605P + I978V mutations have a cumulative, if not synergistic, effect on HEV replication. The Q1246H mutant decreased HEV replication compared to the wild-type HEV Rluc replicon but replicated better than the V1213A mutant. The amino acid residue V1213 favors the replication of both genotypes 3 and 4 HEV strains, but not genotype 1 HEV. Conclusion The results suggested that the V1213A mutation reduced HEV replication, but is likely not associated with the reported severe hepatitis caused by genotype 3 HEV isolates containing this mutation.
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16
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Abstract
Hepatitis E virus (HEV) is a globally important pathogen of acute and chronic hepatitis in humans. The HEV ORF1 gene encodes a nonstructural polyprotein, essential for RNA replication and virus infectivity. Expression and processing of ORF1 polyprotein are shown in prokaryotic and eukaryotic systems, however, its proteolysis into individual proteins is still debated. While molecular or biochemical characterization of methyltransferase, protease, hypervariable region, helicase and RNA polymerase domains in ORF1 has been achieved, the role of the X and Y domains in the HEV life cycle has only been demonstrated very recently. Clinically, detection of a number of ORF1 mutants in infected patients is implicated in disease severity, mortality and drug nonresponse. Moreover, several artificial lethal mutations in ORF1 offer a potential basis for developing live-attenuated vaccines for HEV. This article intends to present the molecular and clinical updates on the HEV ORF1 polyprotein.
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Affiliation(s)
- Mohammad Khalid Parvez
- Department of Pharmacognosy, King Saud University College of Pharmacy, Riyadh 11451, Saudi Arabia
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17
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Borkakoti J, Ahmed G, Kar P. Report of a novel C1483W mutation in the hepatitis E virus polymerase in patients with acute liver failure. INFECTION GENETICS AND EVOLUTION 2016; 44:51-54. [DOI: 10.1016/j.meegid.2016.06.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 06/10/2016] [Accepted: 06/13/2016] [Indexed: 11/29/2022]
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18
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Viral Macro Domains Reverse Protein ADP-Ribosylation. J Virol 2016; 90:8478-86. [PMID: 27440879 DOI: 10.1128/jvi.00705-16] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 07/05/2016] [Indexed: 12/27/2022] Open
Abstract
UNLABELLED ADP-ribosylation is a posttranslational protein modification in which ADP-ribose is transferred from NAD(+) to specific acceptors to regulate a wide variety of cellular processes. The macro domain is an ancient and highly evolutionarily conserved protein domain widely distributed throughout all kingdoms of life, including viruses. The human TARG1/C6orf130, MacroD1, and MacroD2 proteins can reverse ADP-ribosylation by acting on ADP-ribosylated substrates through the hydrolytic activity of their macro domains. Here, we report that the macro domain from hepatitis E virus (HEV) serves as an ADP-ribose-protein hydrolase for mono-ADP-ribose (MAR) and poly(ADP-ribose) (PAR) chain removal (de-MARylation and de-PARylation, respectively) from mono- and poly(ADP)-ribosylated proteins, respectively. The presence of the HEV helicase in cis dramatically increases the binding of the macro domain to poly(ADP-ribose) and stimulates the de-PARylation activity. Abrogation of the latter dramatically decreases replication of an HEV subgenomic replicon. The de-MARylation activity is present in all three pathogenic positive-sense, single-stranded RNA [(+)ssRNA] virus families which carry a macro domain: Coronaviridae (severe acute respiratory syndrome coronavirus and human coronavirus 229E), Togaviridae (Venezuelan equine encephalitis virus), and Hepeviridae (HEV), indicating that it might be a significant tropism and/or pathogenic determinant. IMPORTANCE Protein ADP-ribosylation is a covalent posttranslational modification regulating cellular protein activities in a dynamic fashion to modulate and coordinate a variety of cellular processes. Three viral families, Coronaviridae, Togaviridae, and Hepeviridae, possess macro domains embedded in their polyproteins. Here, we show that viral macro domains reverse cellular ADP-ribosylation, potentially cutting the signal of a viral infection in the cell. Various poly(ADP-ribose) polymerases which are notorious guardians of cellular integrity are demodified by macro domains from members of these virus families. In the case of hepatitis E virus, the adjacent viral helicase domain dramatically increases the binding of the macro domain to PAR and simulates the demodification activity.
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19
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van Tong H, Hoan NX, Wang B, Wedemeyer H, Bock CT, Velavan TP. Hepatitis E Virus Mutations: Functional and Clinical Relevance. EBioMedicine 2016; 11:31-42. [PMID: 27528267 PMCID: PMC5049923 DOI: 10.1016/j.ebiom.2016.07.039] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 07/29/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) infection is a major cause of acute hepatitis and affects more than 20 million individuals, with three million symptomatic cases and 56,000 recognized HEV-related deaths worldwide. HEV is endemic in developing countries and is gaining importance in developed countries, due to increased number of autochthone cases. Although HEV replication is controlled by the host immune system, viral factors (especially specific viral genotypes and mutants) can modulate HEV replication, infection and pathogenesis. Limited knowledge exists on the contribution of HEV genome variants towards pathogenesis, susceptibility and to therapeutic response. Nonsynonymous substitutions can modulate viral proteins structurally and thus dysregulate virus-host interactions. This review aims to compile knowledge and discuss recent advances on the casual role of HEV heterogeneity and its variants on viral morphogenesis, pathogenesis, clinical outcome and antiviral resistance.
HEV causes acute hepatitis and recently comes into focus because of persistent infection in immunocompromised patients. HEV variability can be associated with clinical pathogenesis and transmission dynamics. Mutations in the HEV genome can influence HEV physiology and virus-host interaction. HEV mutations and variability are likely associated with fulminant hepatic failure and chronic hepatitis E. The Y1320H and G1634R/K mutations in the RdRp domain contribute to antiviral resistance through enhancing HEV replication. We searched MEDLINE database and PubMed for articles from 1980 through June 30, 2016. Search terms used in various combinations were “hepatitis E”, “hepatitis E virus”, “hepatitis E virus infection”, “hepatitis E virus mutation”, “HEV variability”, “HEV genotype”, “HEV drug resistance”, “HEV replication” and “ribavirin”. Articles resulting from these searches and relevant references cited in those articles were selected based on their related topics and were reviewed. Abstracts and reports from meetings were also included. Articles published in English were included.
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Affiliation(s)
- Hoang van Tong
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Bo Wang
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - C-Thomas Bock
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany.
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20
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Shimakawa Y, Njai HF, Takahashi K, Berg L, Ndow G, Jeng-Barry A, Ceesay A, Tamba S, Opoku E, Taal M, Akbar SMF, Arai M, D'Alessandro U, Taylor-Robinson SD, Njie R, Mishiro S, Thursz MR, Lemoine M. Hepatitis E virus infection and acute-on-chronic liver failure in West Africa: a case-control study from The Gambia. Aliment Pharmacol Ther 2016; 43:375-84. [PMID: 26623967 DOI: 10.1111/apt.13484] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 09/17/2015] [Accepted: 11/04/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND In sub-Saharan Africa, it is unknown whether hepatitis E virus (HEV) infection is a common precipitating event of acute-on-chronic liver failure (ACLF). AIMS To estimate the prevalence of HEV infection in general population and assess whether HEV is a common trigger of ACLF in cirrhotic patients in The Gambia, West Africa. METHODS We first conducted an HEV sero-survey in healthy volunteers. We then tested cirrhotic patients with ACLF (cases) and compensated cirrhosis (controls) for anti-HEV IgG as a marker of exposure to HEV, and anti-HEV IgA and HEV RNA as a marker of recent infection. We also described the characteristics and survival of the ACLF cases and controls. RESULTS In the healthy volunteers (n = 204), 13.7% (95% CI: 9.6-19.2) were positive for anti-HEV IgG, and none had positive HEV viraemia. After adjusting for age and sex, the following were associated with positive anti-HEV IgG: being a Christian, a farmer, drinking water from wells, handling pigs and eating pork. In 40 cases (median age: 45 years, 72.5% male) and 71 controls (39 years, 74.6% male), ≥70% were infected with hepatitis B virus. Although hepatitis B flare and sepsis were important precipitating events of ACLF, none had marker of acute HEV. ACLF cases had high (70.0%) 28-day mortality. CONCLUSIONS Hepatitis E virus infection is endemic in The Gambia, where both faecal-oral route (contaminated water) and zoonotic transmission (pigs/pork meat) may be important. However, acute HEV was not a common cause of acute-on-chronic liver failure in The Gambia.
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Affiliation(s)
- Y Shimakawa
- MRC Unit The Gambia, Banjul, The Gambia.,Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - H F Njai
- MRC Unit The Gambia, Banjul, The Gambia
| | - K Takahashi
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
| | - L Berg
- MRC Unit The Gambia, Banjul, The Gambia.,Hepatology Unit, Department of Medicine, Imperial College London, London, UK
| | - G Ndow
- MRC Unit The Gambia, Banjul, The Gambia.,Hepatology Unit, Department of Medicine, Imperial College London, London, UK
| | | | - A Ceesay
- MRC Unit The Gambia, Banjul, The Gambia
| | - S Tamba
- MRC Unit The Gambia, Banjul, The Gambia
| | - E Opoku
- MRC Unit The Gambia, Banjul, The Gambia.,Hepatology Unit, Department of Medicine, Imperial College London, London, UK
| | - M Taal
- Ministry of Health and Social Welfare, Banjul, The Gambia
| | - S M F Akbar
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
| | - M Arai
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
| | | | - S D Taylor-Robinson
- Hepatology Unit, Department of Medicine, Imperial College London, London, UK
| | - R Njie
- MRC Unit The Gambia, Banjul, The Gambia.,The Gambia Hepatitis Intervention Study, IARC, c/o MRC Unit, Banjul, The Gambia
| | - S Mishiro
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
| | - M R Thursz
- Hepatology Unit, Department of Medicine, Imperial College London, London, UK
| | - M Lemoine
- MRC Unit The Gambia, Banjul, The Gambia.,Hepatology Unit, Department of Medicine, Imperial College London, London, UK
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21
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Shrestha A, Lama TK, Karki S, Sigdel DR, Rai U, Rauniyar SK, Al-Mahtab M, Takahashi K, Arai M, Akbar SMF, Mishiro S. Hepatitis E epidemic, Biratnagar, Nepal, 2014. Emerg Infect Dis 2015; 21:711-3. [PMID: 25811975 PMCID: PMC4378489 DOI: 10.3201/eid2104.141512] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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22
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[Hepatitis E virus: opinions of the Working Group of the Federal Ministry of Health Blood]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2015; 58:198-218. [PMID: 25608627 DOI: 10.1007/s00103-014-2103-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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23
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Smith DB, Ijaz S, Tedder RS, Hogema B, Zaaijer HL, Izopet J, Bradley-Stewart A, Gunson R, Harvala H, Kokki I, Simmonds P. Variability and pathogenicity of hepatitis E virus genotype 3 variants. J Gen Virol 2015; 96:3255-3264. [PMID: 26282123 PMCID: PMC4806580 DOI: 10.1099/jgv.0.000264] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Infection with hepatitis E virus (HEV) can be clinically inapparent or produce symptoms and signs of hepatitis of varying severity and occasional fatality. This variability in clinical outcomes may reflect differences in host susceptibility or the presence of virally encoded determinants of pathogenicity. Analysis of complete genome sequences supports the division of HEV genotype 3 (HEV-3) variants into three major clades: 3ra comprising HEV isolates from rabbits, and 3efg and 3abchij comprising the corresponding named subtypes derived from humans and pigs. Using this framework, we investigated associations between viral genetic variability of HEV-3 in symptomatic and asymptomatic infections by comparing HEV-3 subgenomic sequences previously obtained from blood donors with those from patients presenting with hepatitis in the UK (54 blood donors, 148 hepatitis patients), the Netherlands (38 blood donors, 119 hepatitis patients), France (24 blood donors, 55 hepatitis patients) and Germany (14 blood donors, 36 hepatitis patients). In none of these countries was evidence found for a significant association between virus variants and patient group (P>0.05 Fisher's exact test). Furthermore, within a group of 123 patients in Scotland with clinically apparent HEV infections, we found no evidence for an association between variants of HEV-3 and disease severity or alanine aminotransferase level. The lack of detectable virally encoded determinants of disease outcomes in HEV-3 infection implies a more important role for host factors in its clinical phenotype.
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Affiliation(s)
- Donald B Smith
- University of Edinburgh, CIIE, Ashworth Laboratories, King's Buildings, Edinburgh EH9 3FL, UK
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, MS-Colindale, Public Health England, London NW9 5EQ, UK
| | - Richard S Tedder
- Blood Borne Virus Unit, Virus Reference Department, MS-Colindale, Public Health England, London NW9 5EQ, UK.,University College London, Gower Street, London WC1E 6BT, UK
| | - Boris Hogema
- Department of Blood-borne Infections, Sanquin Research, PO Box 9190, 1006 AD Amsterdam, The Netherlands
| | - Hans L Zaaijer
- Department of Blood-borne Infections, Sanquin Research, PO Box 9190, 1006 AD Amsterdam, The Netherlands
| | - Jacques Izopet
- Institut National de la Sante et de la Recherche Medicale Unite 1043, Toulouse, France
| | | | - Rory Gunson
- West of Scotland Specialist Virology Centre, New Lister Building, Glasgow, UK
| | - Heli Harvala
- Specialist Virology Centre, Royal Infirmary of Edinburgh, UK.,Public Health Agency of Sweden (previously Swedish Institute for Communicable Disease Control), Solna, Sweden.,European Programme for Public Health Microbiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden
| | - Inka Kokki
- Specialist Virology Centre, Royal Infirmary of Edinburgh, UK
| | - Peter Simmonds
- University of Edinburgh, Roslin Institute, Easter Bush, Edinburgh EH25 9RG, UK
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24
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Pauli G, Aepfelbacher M, Bauerfeind U, Blümel J, Burger R, Gärtner B, Gröner A, Gürtler L, Heiden M, Hildebrandt M, Jansen B, Offergeld R, Schlenkrich U, Schottstedt V, Seitz R, Strobel J, Willkommen H, Baylis SA. Hepatitis E Virus. Transfus Med Hemother 2015; 42:247-65. [PMID: 26557817 DOI: 10.1159/000431191] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 02/10/2015] [Indexed: 12/12/2022] Open
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25
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Vina-Rodriguez A, Schlosser J, Becher D, Kaden V, Groschup MH, Eiden M. Hepatitis E virus genotype 3 diversity: phylogenetic analysis and presence of subtype 3b in wild boar in Europe. Viruses 2015; 7:2704-26. [PMID: 26008708 PMCID: PMC4452927 DOI: 10.3390/v7052704] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 05/13/2015] [Accepted: 05/20/2015] [Indexed: 12/14/2022] Open
Abstract
An increasing number of indigenous cases of hepatitis E caused by genotype 3 viruses (HEV-3) have been diagnosed all around the word, particularly in industrialized countries. Hepatitis E is a zoonotic disease and accumulating evidence indicates that domestic pigs and wild boars are the main reservoirs of HEV-3. A detailed analysis of HEV-3 subtypes could help to determine the interplay of human activity, the role of animals as reservoirs and cross species transmission. Although complete genome sequences are most appropriate for HEV subtype determination, in most cases only partial genomic sequences are available. We therefore carried out a subtype classification analysis, which uses regions from all three open reading frames of the genome. Using this approach, more than 1000 published HEV-3 isolates were subtyped. Newly recovered HEV partial sequences from hunted German wild boars were also included in this study. These sequences were assigned to genotype 3 and clustered within subtype 3a, 3i and, unexpectedly, one of them within the subtype 3b, a first non-human report of this subtype in Europe.
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Affiliation(s)
- Ariel Vina-Rodriguez
- Institute for Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
| | - Josephine Schlosser
- Institute for Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
| | - Dietmar Becher
- Micromun GmbH, Greifswald, Walther-Rathenau-Straße 49A, 17489 Greifswald, Germany.
| | - Volker Kaden
- Institute of Infectology, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
| | - Martin H Groschup
- Institute for Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
| | - Martin Eiden
- Institute for Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Südufer 10, 17493 Greifswald-Insel Riems, Germany.
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26
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Analysis of complete genome sequences and a V239A substitution in the helicase domain of swine hepatitis E virus strains isolated in Canada. Arch Virol 2015; 160:1767-73. [PMID: 25916609 DOI: 10.1007/s00705-015-2429-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 04/11/2015] [Indexed: 10/23/2022]
Abstract
Among Canadian swine HEV strains, only one complete genome sequence has been published so far, and there are no data on the virulence of these strains. A collection of 28 Canadian swine HEV strains was used in this study. After RNA extraction, a portion of ORF2, the 3' end of the helicase domain, and two complete genomes were amplified and sequenced. These two new Canadian complete genomes belonged to two different subtypes and showed 87.5 and 87.7% sequence identity to the Canadian swine HEV strain Arkell. The V239A substitution within the helicase domain, which is associated with increased virulence of genotype 3 HEV, was detected in one Canadian swine HEV strain. However, no human hepatitis E infections have been associated with this strain.
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27
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Smith DB, Simmonds P. Hepatitis E virus and fulminant hepatitis--a virus or host-specific pathology? Liver Int 2015; 35:1334-40. [PMID: 24974734 PMCID: PMC4676335 DOI: 10.1111/liv.12629] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 06/18/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Fulminant hepatitis is a rare outcome of infection with hepatitis E virus. Several recent reports suggest that virus variation is an important determinant of disease progression. To critically examine the evidence that virus-specific factors underlie the development of fulminant hepatitis following hepatitis E virus infection. METHODS Published sequence information of hepatitis E virus isolates from patients with and without fulminant hepatitis was collected and analysed using statistical tests to identify associations between virus polymorphisms and disease outcome. RESULTS Fulminant hepatitis has been reported following infection with all four hepatitis E virus genotypes that infect humans comprising multiple phylogenetic lineages within genotypes 1, 3 and 4. Analysis of virus sequences from individuals infected by a common source did not detect any common substitutions associated with progression to fulminant hepatitis. Re-analysis of previously reported associations between virus substitutions and fulminant hepatitis suggests that these were probably the result of sampling biases. CONCLUSIONS Host-specific factors rather than virus genotype, variants or specific substitutions appear to be responsible for the development of fulminant hepatitis.
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Affiliation(s)
- Donald B Smith
- Centre for Immunity, Infection and Evolution, Ashworth Laboratories, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JT, UK
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Novel molecular alterations in the ORF 2 capsid gene of hepatitis E virus in patients with acute liver failure in North India. Arch Virol 2014; 159:3391-4. [DOI: 10.1007/s00705-014-2198-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 07/29/2014] [Indexed: 10/24/2022]
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Johne R, Dremsek P, Reetz J, Heckel G, Hess M, Ulrich RG. Hepeviridae: an expanding family of vertebrate viruses. INFECTION GENETICS AND EVOLUTION 2014; 27:212-29. [PMID: 25050488 DOI: 10.1016/j.meegid.2014.06.024] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 06/25/2014] [Accepted: 06/26/2014] [Indexed: 12/15/2022]
Abstract
The hepatitis E virus (HEV) was first identified in 1990, although hepatitis E-like diseases in humans have been recorded for a long time dating back to the 18th century. The HEV genotypes 1-4 have been subsequently detected in human hepatitis E cases with different geographical distribution and different modes of transmission. Genotypes 3 and 4 have been identified in parallel in pigs, wild boars and other animal species and their zoonotic potential has been confirmed. Until 2010, these genotypes along with avian HEV strains infecting chicken were the only known representatives of the family Hepeviridae. Thereafter, additional HEV-related viruses have been detected in wild boars, distinct HEV-like viruses were identified in rats, rabbit, ferret, mink, fox, bats and moose, and a distantly related agent was described from closely related salmonid fish. This review summarizes the characteristics of the so far known HEV-like viruses, their phylogenetic relationship, host association and proposed involvement in diseases. Based on the reviewed knowledge, a suggestion for a new taxonomic grouping scheme of the viruses within the family Hepeviridae is presented.
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Affiliation(s)
- Reimar Johne
- Federal Institute for Risk Assessment, Berlin, Germany
| | - Paul Dremsek
- Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany
| | - Jochen Reetz
- Federal Institute for Risk Assessment, Berlin, Germany
| | - Gerald Heckel
- University of Bern, Institute of Ecology and Evolution, Bern, Switzerland; Swiss Institute of Bioinformatics, Genopode, Lausanne, Switzerland
| | - Michael Hess
- Clinic for Poultry and Fish Medicine, Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine (Vetmeduni Vienna), Vienna, Austria
| | - Rainer G Ulrich
- Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany.
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Lara J, Purdy MA, Khudyakov YE. Genetic host specificity of hepatitis E virus. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2014; 24:127-39. [PMID: 24667049 PMCID: PMC5745802 DOI: 10.1016/j.meegid.2014.03.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 02/24/2014] [Accepted: 03/16/2014] [Indexed: 01/06/2023]
Abstract
Hepatitis E virus (HEV) causes epidemic and sporadic cases of hepatitis worldwide. HEV genotypes 3 (HEV3) and 4 (HEV4) infect humans and animals, with swine being the primary reservoir. The relevance of HEV genetic diversity to host adaptation is poorly understood. We employed a Bayesian network (BN) analysis of HEV3 and HEV4 to detect epistatic connectivity among protein sites and its association with the host specificity in each genotype. The data imply coevolution among ∼70% of polymorphic sites from all HEV proteins and association of numerous coevolving sites with adaptation to swine or humans. BN models for individual proteins and domains of the nonstructural polyprotein detected the host origin of HEV strains with accuracy of 74-93% and 63-87%, respectively. These findings, taken together with lack of phylogenetic association to host, suggest that the HEV host specificity is a heritable and convergent phenotypic trait achievable through variety of genetic pathways (abundance), and explain a broad host range for HEV3 and HEV4.
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Affiliation(s)
- James Lara
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA.
| | - Michael A Purdy
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Yury E Khudyakov
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
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31
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Analysis of helicase domain mutations in the hepatitis E virus derived from patients with fulminant hepatic failure: effects on enzymatic activities and virus replication. Virus Res 2014; 184:103-10. [PMID: 24630891 PMCID: PMC7172619 DOI: 10.1016/j.virusres.2014.02.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Revised: 02/19/2014] [Accepted: 02/19/2014] [Indexed: 12/30/2022]
Abstract
Effect of fulminant hepatic failure (FHF) associated mutations on helicase activities and virus replication were checked. All the FHF mutants showed comparable unwinding activities with the wild type protein despite the differences in ATPase activities. All the FHF mutant replicons showed marginal decrease in virus replication compared to the wild type replicon suggesting alternate function/s of the helicase protein. Walker A motif and Walker B motif in the helicase domain are indispensable for HEV replication. Fulminant hepatic failure (FHF) is the severe form of hepatitis E virus infection. Virus sequence analyses from severe cases have shown presence of unique and highly conserved mutations in the helicase domain of genotype 1, 3 and 4 viruses. We evaluated role of two amino acid replacements (L1110F) and (V1120I); found to be frequent in genotype 1 FHF-E viruses from India. Three mutant helicase proteins (two with single point mutations and one with dual mutations) were expressed in Escherichia coli and evaluated for their ATPase and RNA unwinding activities. Both L1110F and V1120I helicase mutants showed marginal decrease in ATPase activity, while L1110F/V1120I dual mutant showed normal ATPase activity. All three mutants proteins showed RNA unwinding activities comparable to wild type protein. Corresponding mutations were made in the helicase domain of HEV RLuc replicon and replication efficiencies were tested in the S10-3 (Huh 7) cells. The mutant replicon V1120I showed lower replication as compared to L1110F and L1110F/V1120I mutants. However, all three replicon mutants showed lower replication efficiencies as compared to the wild type replicon. Walker A and Walker B motif mutant HEV replicons were unable to replicate indicating essential role of the virus encoded helicase domain during HEV replication. FHF-E associated helicase mutations resulted in only marginal decrease in the virus replication suggesting alternate function/s of the helicase protein. Mutations in the helicase domain of FHF-E viruses may be responsible for changing virus or host-virus protein–protein interactions, causing alterations in the host responses, eventually leading to more severe disease manifestations.
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Aherfi S, Borentain P, Raissouni F, Le Goffic A, Guisset M, Renou C, Grimaud JC, Hardwigsen J, Garcia S, Botta-Fridlund D, Nafati C, Motte A, Le Treut YP, Colson P, Gerolami R. Liver transplantation for acute liver failure related to autochthonous genotype 3 hepatitis E virus infection. Clin Res Hepatol Gastroenterol 2014; 38:24-31. [PMID: 24462173 DOI: 10.1016/j.clinre.2013.05.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 04/28/2013] [Accepted: 05/14/2013] [Indexed: 02/04/2023]
Abstract
Hepatitis E virus of genotype 3 (HEV-3) is an emerging cause of sporadic autochthonous acute hepatitis in Europe. Although spontaneous outcome of hepatitis E is usually favorable, fulminant liver failure has been described worldwide. In Europe, autochthonous hepatitis E associated with fulminant hepatic failure and leading to liver transplantation has been exceptionally reported. We report here four cases of fulminant and sub-fulminant hepatitis E proposed for liver transplantation in Marseille University hospitals between July 2006 and March 2010. HEV diagnosis relied on detection of anti-HEV IgM antibodies and HEV RNA in serum samples. All cases were men, with no travel history in hyperendemic areas. HEV sequence analyses revealed genotype 3 HEV in the four patients. Liver histology indicated severe acute hepatitis in all of them, pre-existing fibrosis being found in two cases. Two patients underwent liver transplantation, and the two other patients could not be transplanted due to septic complications and died. HEV testing should be performed for the initial evaluation of every acute liver failure regardless of the epidemiological and clinical context. With respect to the potentially fulminant evolution of HEV genotype 3 infections, treatment with ribavirin of severe acute hepatitis E should be considered.
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Affiliation(s)
- Sarah Aherfi
- Institut hospitalo-universitaire (IHU) Méditerranée Infection, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, Assistance publique-Hôpitaux de Marseille, centre hospitalo-universitaire Timone, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France
| | - Patrick Borentain
- Service d'hépatogastroentérologie, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Ferdaous Raissouni
- Service d'hépatogastroentérologie, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Aude Le Goffic
- Service d'hépatogastroentérologie, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Michel Guisset
- Service de pathologie digestive, hôpital d'instruction des armées Laveran, BP 60149, 13384 Marseille cedex 13, France
| | - Christophe Renou
- Hôpital de jour, centre hospitalier de Hyères, 8, rue Maréchal-Juin, Hyères, France
| | - Jean-Charles Grimaud
- Service d'hépatogastroentérologie, centre hospitalo-universitaire Nord, chemin des Bourrelys, 13915 Marseille cedex 20, France
| | - Jean Hardwigsen
- Service de transplantation hépatique, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Stéphane Garcia
- Service d'anatomopathologie, centre hospitalo-universitaire Nord, chemin des Bourrely, 13015 Marseille, France
| | - Danielle Botta-Fridlund
- Service d'hépatogastroentérologie, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Cyril Nafati
- Service de réanimation, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Anne Motte
- Institut hospitalo-universitaire (IHU) Méditerranée Infection, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, Assistance publique-Hôpitaux de Marseille, centre hospitalo-universitaire Timone, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France
| | - Yves Patrice Le Treut
- Service de transplantation hépatique, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Philippe Colson
- Institut hospitalo-universitaire (IHU) Méditerranée Infection, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, Assistance publique-Hôpitaux de Marseille, centre hospitalo-universitaire Timone, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France; Aix-Marseille Université, URMITE UM63 CNRS 7278 IRD 198 Inserm U1095, facultés de médecine et de pharmacie, 27, boulevard Jean-Moulin, 13385 Marseille cedex 05, France.
| | - René Gerolami
- Service d'hépatogastroentérologie, centre hospitalo-universitaire Conception, 147, boulevard Baille, 13385 Marseille cedex 05, France.
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Umemura M, Watanabe Y, Ogawa K, Yamamoto Y, Yawata A, Einami K, Nagasako T, Kawamura N, Kudo M, Matsubayashi K, Karino Y, Kan JH, Mizuo H, Okamoto H, Takahashi K, Abe N, Arai M, Mishiro S. Occurrence of acute hepatitis E virus infection in the Hakodate district: A prospective study of four hospitals in Hakodate City. ACTA ACUST UNITED AC 2014. [DOI: 10.2957/kanzo.55.349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Krain LJ, Nelson KE, Labrique AB. Host immune status and response to hepatitis E virus infection. Clin Microbiol Rev 2014; 27:139-65. [PMID: 24396140 PMCID: PMC3910912 DOI: 10.1128/cmr.00062-13] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatitis E virus (HEV), identified over 30 years ago, remains a serious threat to life, health, and productivity in developing countries where access to clean water is limited. Recognition that HEV also circulates as a zoonotic and food-borne pathogen in developed countries is more recent. Even without treatment, most cases of HEV-related acute viral hepatitis (with or without jaundice) resolve within 1 to 2 months. However, HEV sometimes leads to acute liver failure, chronic infection, or extrahepatic symptoms. The mechanisms of pathogenesis appear to be substantially immune mediated. This review covers the epidemiology of HEV infection worldwide, the humoral and cellular immune responses to HEV, and the persistence and protection of antibodies produced in response to both natural infection and vaccines. We focus on the contributions of altered immune states (associated with pregnancy, human immunodeficiency virus [HIV], and immunosuppressive agents used in cancer and transplant medicine) to the elevated risks of chronic infection (in immunosuppressed/immunocompromised patients) and acute liver failure and mortality (among pregnant women). We conclude by discussing outstanding questions about the immune response to HEV and interactions with hormones and comorbid conditions. These questions take on heightened importance now that a vaccine is available.
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Affiliation(s)
- Lisa J. Krain
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Kenrad E. Nelson
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Alain B. Labrique
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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35
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Harun-Or-Rashid M, Akbar SMF, Takahashi K, Al-Mahtab M, Khan MSI, Alim MA, Ekram ARMS, Khan MMR, Arai M, Mishiro S. Epidemiological and molecular analyses of a non-seasonal outbreak of acute icteric hepatitis E in Bangladesh. J Med Virol 2013; 85:1369-76. [PMID: 23703666 DOI: 10.1002/jmv.23601] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2013] [Indexed: 11/08/2022]
Affiliation(s)
| | | | - Kazuaki Takahashi
- Department of Medical Sciences; Toshiba General Hospital; Tokyo Japan
| | - Mamun Al-Mahtab
- Department of Hepatology; Bangabandhu Sheikh Mujib Medical University; Dhaka Bangladesh
| | | | | | | | | | - Masahiro Arai
- Department of Medical Sciences; Toshiba General Hospital; Tokyo Japan
| | - Shunji Mishiro
- Department of Medical Sciences; Toshiba General Hospital; Tokyo Japan
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Rodríguez-Frias F, Jardi R, Buti M. [Hepatitis E: molecular virology, epidemiology and pathogenesis]. Enferm Infecc Microbiol Clin 2012; 30:624-34. [PMID: 22386306 DOI: 10.1016/j.eimc.2012.01.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 01/11/2012] [Accepted: 01/18/2012] [Indexed: 02/07/2023]
Abstract
Hepatitis E represents a significant proportion of enteric transmitted liver diseases and poses a major public health problem, mainly associated with epidemics due to contamination of water supplies, especially in developing countries. Hepatitis E virus (HEV) is responsible for self-limiting acute liver oral-faecal infections. In industrialised countries, acute hepatitis E is sporadic, detected in travellers from endemic areas but also in sporadic cases with no risk factors. HEV is a non-enveloped virus with a single-stranded RNA genome classified into 4 genotypes and a single serotype. Genotypes 1 and 2 only infect humans, and are predominant in the developing countries, while 3 and 4 are predominant in industrialised countries, and also infect other species of mammals, especially pigs, and multiple evidence classifies HEV as a zoonotic agent. Some HEV chronic infections have recently been reported in kidney and liver transplant patients. The mortality rate of HEV infection is greater than hepatitis A. In addition to faecal-oral transmission, parenteral transmission of HEV has also been reported. Several vaccines are currently in development. The severity of this infection in some groups of patients, especially pregnant women, and the occurrence of chronic hepatitis, even with progression to cirrhosis, have raised interest in the application of interferon and/or ribavirin therapy.
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Affiliation(s)
- Francisco Rodríguez-Frias
- Unidad de Proteínas Hepatitis, Servicio de Bioquímica, Hospital Universitario Vall d'Hebron, Barcelona, España.
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Hepatitis E virus from India exhibits significant amino acid mutations in fulminant hepatic failure patients. Virus Genes 2012; 46:47-53. [DOI: 10.1007/s11262-012-0833-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Accepted: 09/29/2012] [Indexed: 11/25/2022]
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Hoshino H, Hino K, Miyakawa H, Takahashi K, Akbar SMF, Mishiro S. Inter-genotypic recombinant hepatitis C virus strains in Japan noted by discrepancies between immunoassay and sequencing. J Med Virol 2012; 84:1018-24. [PMID: 22585717 DOI: 10.1002/jmv.23300] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Genetic recombination plays a significant role in the survival and evolution of hepatitis C virus (HCV), but methodological limitations have hindered the exploration of genetic recombination. HCV serotypes were evaluated in 104 patients with chronic hepatitis C when they initially presented in hospitals. Subsequently, HCV genotypes were analyzed using primers for core gene and NS5B gene. Near-complete nucleotide sequences of eight HCV isolates from two suspected patients with 2b/1b recombinant HCV were analyzed by amplification of nine overlapping regions of HCV-specific oligonucleotide primers at different time points: (i) at the first admission; (ii) before and (iii) after interferon therapy; and (iv) after development of hepatocellular carcinoma. The nucleotide sequence of eight HCV isolates obtained was 9,321-9,471 nucleotides in length, comprising a single ORF (polyprotein of 3,014 amino acids.) and segregated into discordant genotypes of 2b and 1b HCV with a recombination junction in NS2. This study highlights the need for more precise characterization of HCV in clinical samples where there is a discrepancy between immunoassays and sequencing. It also demonstrates the circulation of novel inter-genotypic recombinant HCV in Japan, because the cross over point of 2b/1b recombinant HCV in eight clinical isolates of these two patients differed from previously reported HCV recombinant from the Philippines and Japan.
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Purdy MA, Khudyakov YE. The molecular epidemiology of hepatitis E virus infection. Virus Res 2011; 161:31-9. [PMID: 21600939 DOI: 10.1016/j.virusres.2011.04.030] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Revised: 03/23/2011] [Accepted: 04/29/2011] [Indexed: 12/11/2022]
Abstract
Molecular characterization of various hepatitis E virus (HEV) strains circulating among humans and animals (particularly swine, deer and boars) in different countries has revealed substantial genetic heterogeneity. The distinctive four-genotype distribution worldwide of mammalian HEV and varying degrees of genetic relatedness among local strains suggest a long and complex evolution of HEV in different geographic regions. The population expansion likely experienced by mammalian HEV in the second half of the 20th century is consistent with an extensive genetic divergence of HEV strains and high prevalence of HEV infections in many parts of the world, including developed countries. The rate and mechanisms of human-to-human transmission and zoonotic transmission to humans vary geographically, thus contributing to the complexity of HEV molecular evolution.
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Affiliation(s)
- Michael A Purdy
- Centers for Disease Control and Prevention, National Center for HIV/Hepatitis/STD/TB Prevention, Division of Viral Hepatitis, Atlanta, GA 30333, USA.
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Zhang W, He Y, Wang H, Shen Q, Cui L, Wang X, Shao S, Hua X. Hepatitis E virus genotype diversity in eastern China. Emerg Infect Dis 2011; 16:1630-2. [PMID: 20875298 PMCID: PMC3294409 DOI: 10.3201/eid1610.100873] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We studied 47 hepatitis E virus (HEV) isolates from hospitalized patients in Nanjing and Taizhou, eastern China. Genotypes 1, 3, and 4 were prevalent; genotype 3 and subgenotype 4b showed a close relationship with the swine strains in eastern China, thus indicating that HEV genotype 3 had infected humans in China.
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Affiliation(s)
- Wen Zhang
- School of Medical Science and Laboratory Medicine, Jiangsu University, Jiangsu, People's Republic of China.
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41
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Okano H, Nakano T, Matsusaki S, Sase T, Saitou T, Mukai K, Nishimura A, Ito K, Shiraki K, Takei Y, Okamoto H. Four cases of sporadic acute hepatitis E in Mie, Japan who were infected with European type genotype 3 hepatitis E virus. ACTA ACUST UNITED AC 2011. [DOI: 10.2957/kanzo.52.295] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Rolfe KJ, Curran MD, Mangrolia N, Gelson W, Alexander GJM, L'estrange M, Vivek R, Tedder R, Ijaz S. First case of genotype 4 human hepatitis E virus infection acquired in India. J Clin Virol 2010; 48:58-61. [PMID: 20227909 DOI: 10.1016/j.jcv.2010.02.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 02/01/2010] [Accepted: 02/04/2010] [Indexed: 12/29/2022]
Abstract
This report describes a case of severe hepatitis in an individual returning from India which was found to be the result of infection with HEV genotype 4. HEV was diagnosed using a novel RT-PCR assay (with internal control) for HEV RNA detection/quantitation, described herein. This is the first documented report of zoonotic transmission of HEV genotype 4 infection acquired in India.
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Affiliation(s)
- K J Rolfe
- Clinical Microbiology and Public Health Laboratory, Health Protection Agency, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QW, UK.
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Takahashi M, Tamura K, Hoshino Y, Nagashima S, Yazaki Y, Mizuo H, Iwamoto S, Okayama M, Nakamura Y, Kajii E, Okamoto H. A nationwide survey of hepatitis E virus infection in the general population of Japan. J Med Virol 2010; 82:271-81. [PMID: 20029817 DOI: 10.1002/jmv.21678] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
To investigate nationwide the prevalence of hepatitis E virus (HEV) infection in the general population of Japan, serum samples were collected from 22,027 individuals (9,686 males and 12,341 females; age, mean +/- standard deviation: 56.8 +/- 16.7 years; range: 20-108 years) who lived in 30 prefectures located in Hokkaido, mainland Honshu, Shikoku, and Kyushu of Japan and underwent health check-ups during 2002-2007, and were tested for the presence of IgG, IgM, and IgA classes of antibodies to HEV (anti-HEV) by in-house ELISA and HEV RNA by nested RT-PCR. Overall, 1,167 individuals (5.3%) were positive for anti-HEV IgG, including 753 males (7.8%) and 414 females (3.4%), the difference being statistically significant (P < 0.0001). The prevalence of anti-HEV IgG generally increased with age and was significantly higher among individuals aged >or=50 years than among those aged <50 years (6.6% vs. 2.7%, P < 0.0001). Although 13 individuals with anti-HEV IgG also had anti-HEV IgM and/or anti-HEV IgA, none of them had detectable HEV RNA. The presence of HEV RNA was further tested in 50 or 49-sample minipools of sera from the remaining 22,014 individuals, and three individuals without anti-HEV antibodies tested positive for HEV RNA. The HEV isolates obtained from the three viremic individuals segregated into genotype 3 and were closest to Japan-indigenous HEV strains. When stratified by geographic region, the prevalence of anti-HEV IgG as well as the prevalence of HEV RNA or anti-HEV IgM and/or anti-HEV IgA was significantly higher in northern Japan than in southern Japan (6.7% vs. 3.2%, P < 0.0001; 0.11% vs. 0.01%, P = 0.0056; respectively).
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Affiliation(s)
- Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi-Ken, Japan
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Brost S, Wenzel JJ, Ganten TM, Filser M, Flechtenmacher C, Boehm S, Astani A, Jilg W, Zeier M, Schnitzler P. Sporadic cases of acute autochthonous hepatitis E virus infection in Southwest Germany. J Clin Virol 2009; 47:89-92. [PMID: 19910247 DOI: 10.1016/j.jcv.2009.10.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 10/05/2009] [Accepted: 10/07/2009] [Indexed: 02/03/2023]
Abstract
Hepatitis E infection is usually a self-limiting disease and an important cause of acute hepatitis in tropical and subtropical regions where the virus is endemic. In industrialized countries, sporadic cases of acute hepatitis E virus (HEV) infections have been described and the number of documented autochthonous infections seems to be increasing. We report three sporadic cases of autochthonous hepatitis E infections in Southwestern Germany which presented at our university hospital within two years. All cases were men who presented with acute hepatitis, icterus and elevated liver. In case 1 and case 2, liver biopsy revealed acute hepatitis, both patients were positive for anti-HEV antibodies, case 1 was also positive for HEV RNA with a viral load of 3.0 x 10(3)copies/ml in serum. In case 3, anti-HEV antibodies were detectable and HEV RNA was detected in serum (4.3 x 10(3)copies/ml) and stool (1.4 x 10(6)copies/ml). None of the patients had a recent travel history outside Germany and close contact to animals has been denied. HEV sequence analysis of two patients revealed genotype 3 with homologies to other European isolates and isolates from swine. Thus the source of infection remains unclear. Hepatitis E should be considered in differential diagnosis in patients with unexplained hepatitis and patients with acute hepatitis, whatever their age or travel history might be, should be tested for HEV.
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Affiliation(s)
- S Brost
- Department of Internal Medicine IV, University of Heidelberg, Heidelberg, Germany
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Sugawara N, Yawata A, Takahashi K, Abe N, Arai M. The third case of fulminant hepatitis associated with "Kitami/Abashiri strain" of hepatitis E virus genotype 4. ACTA ACUST UNITED AC 2009. [DOI: 10.2957/kanzo.50.473] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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