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Ankavay M, Da Silva N, Pollán A, Oechslin N, Dinkelborg K, Behrendt P, Moradpour D, Gouttenoire J. Monitoring of hepatitis E virus infection and replication by functional tagging of the ORF2 protein. JHEP Rep 2025; 7:101293. [PMID: 39991067 PMCID: PMC11847060 DOI: 10.1016/j.jhepr.2024.101293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 11/25/2024] [Accepted: 11/28/2024] [Indexed: 02/25/2025] Open
Abstract
Background and Aims Hepatitis E virus (HEV) infection is a leading cause of acute hepatitis worldwide. Understanding of the mechanisms underlying productive HEV infection remains incomplete and would benefit from technological advances improving current model systems. Methods We exploited transposon-mediated random insertion and selection of viable clones to identify sites in the HEV open reading frame 2 (ORF2) protein, corresponding to the viral capsid, allowing for the insertion of reporter sequences in a functional context. Results Short sequence insertions (5 amino acids) were tolerated at four distinct sites in the C-terminal region of the ORF2 protein, without significantly affecting viral capsid expression and subcellular localization as well as virus production. Full-length HEV genomes harboring larger sequence insertions such as an HA epitope tag, a highly sensitive miniaturized luciferase reporter (HiBiT) or a split GFP at these sites conserved their ability to produce infectious virus, with about a 1-log decrease in viral titers. Findings were confirmed in two different HEV genotype 3 clones. In addition, we demonstrate that HiBiT-tagged HEV, offering rapid and several-log amplitude detection, can be used for the evaluation of antiviral drugs and neutralizing antibodies. Conclusions We describe a convenient, quantitative and potentially scalable system for the monitoring of HEV infection and replication in tissue culture. Impact and implications Hepatitis E virus infection is one of the most frequent causes of acute hepatitis and jaundice worldwide. As treatment options are limited and a vaccine is not universally available, the development of molecular tools to facilitate the identification of new therapeutic strategies is crucial. Based on a screening approach to identify viable insertion sites in the viral genome, we describe a versatile system for preparing recombinant viruses harboring split-reporter tags, i.e. luciferase and GFP. Proof-of-concept experiments revealed that convenient and quantitative monitoring of viral infection and replication is possible with this system, allowing for the evaluation of antiviral drugs and neutralizing antibodies.
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Affiliation(s)
- Maliki Ankavay
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nathalie Da Silva
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Angela Pollán
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Noémie Oechslin
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Katja Dinkelborg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School and Institute for Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School and Institute for Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jérôme Gouttenoire
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Frericks N, Klöhn M, Lange F, Pottkämper L, Carpentier A, Steinmann E. Host-targeting antivirals for chronic viral infections of the liver. Antiviral Res 2025; 234:106062. [PMID: 39716667 DOI: 10.1016/j.antiviral.2024.106062] [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: 11/29/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 12/25/2024]
Abstract
Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.
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Affiliation(s)
- Nicola Frericks
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Frauke Lange
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Lilli Pottkämper
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Arnaud Carpentier
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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Castagna F, Liguori G, Lombardi R, Bava R, Costagliola A, Giordano A, Quintiliani M, Giacomini D, Albergo F, Gigliotti A, Lupia C, Ceniti C, Tilocca B, Palma E, Roncada P, Britti D. Hepatitis E and Potential Public Health Implications from a One-Health Perspective: Special Focus on the European Wild Boar ( Sus scrofa). Pathogens 2024; 13:840. [PMID: 39452712 PMCID: PMC11510200 DOI: 10.3390/pathogens13100840] [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: 08/14/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
The hepatitis E virus (HEV) has become increasingly important in recent years in terms of risk for public health, as the main causative agent of acute viral hepatitis. It is a foodborne disease transmitted to humans through the consumption of contaminated water or contaminated food. Human-to-human transmission is sporadic and is linked to transfusions or transplants. The main reservoirs of the hepatitis E virus are domestic pigs and wild boars, although, compared to pigs, wild boars represent a lesser source of risk since their population is smaller and the consumption of derived products is more limited. These peculiarities often make the role of the wild boar reservoir in the spread of the disease underestimated. As a public health problem that involves several animal species and humans, the management of the disease requires an interdisciplinary approach, and the concept of "One Health" must be addressed. In this direction, the present review intends to analyze viral hepatitis E, with a particular focus on wild boar. For this purpose, literature data have been collected from different scientific search engines: PubMed, MEDLINE, and Google scholar, and several keywords such as "HEV epidemiology", "Extrahepatic manifestations of Hepatitis E", and "HEV infection control measures", among others, have been used. In the first part, the manuscript provides general information on the disease, such as epidemiology, transmission methods, clinical manifestations and implications on public health. In the second part, it addresses in more detail the role of wild boar as a reservoir and the implications related to the virus epidemiology. The document will be useful to all those who intend to analyze this infectious disease from a "One-Health" perspective.
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Affiliation(s)
- Fabio Castagna
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
- Mediterranean Ethnobotanical Conservatory, 88054 Catanzaro, Italy;
| | - Giovanna Liguori
- Local Health Authority, ASL, 71121 Foggia, Italy; (G.L.); (R.L.)
| | - Renato Lombardi
- Local Health Authority, ASL, 71121 Foggia, Italy; (G.L.); (R.L.)
| | - Roberto Bava
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Anna Costagliola
- Department of Veterinary Medicine and Animal Productions, University of Napoli Federico II, 80100 Naples, Italy;
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, 1900 N 12th Street, Philadelphia, PA 19122, USA;
- Department of Medical Biotechnology, University of Siena, 10100 Siena, Italy
| | | | | | - Francesco Albergo
- Department of Management, Finance and Technology, University LUM Giuseppe Degennaro, 70100 Casamassima, Italy;
| | - Andrea Gigliotti
- Interregional Park of Sasso Simone and Simoncello, 61021 Carpegna, Italy;
| | - Carmine Lupia
- Mediterranean Ethnobotanical Conservatory, 88054 Catanzaro, Italy;
| | - Carlotta Ceniti
- ASL Napoli 3 SUD, Department of Prevention, 80053 Castellammare di Stabia, Italy;
| | - Bruno Tilocca
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Ernesto Palma
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Paola Roncada
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Domenico Britti
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. S2k-Leitlinie Lebertransplantation der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Ziersch M, Harms D, Neumair L, Kurreck A, Johne R, Bock CT, Kurreck J. Combining RNA Interference and RIG-I Activation to Inhibit Hepatitis E Virus Replication. Viruses 2024; 16:1378. [PMID: 39339854 PMCID: PMC11435946 DOI: 10.3390/v16091378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/19/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. In the absence of specific antiviral treatments, the exploration of RNAi interference (RNAi) as a targeted strategy provides valuable insights for urgently needed therapeutic interventions against Hepatitis E. We designed small interfering RNAs (siRNAs) against HEV, which target the helicase domain and the open reading frame 3 (ORF3). These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5' triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. This dual-action strategy, combining the activation of the adaptive immune response and the inherent RNAi pathway, inhibits HEV replication successfully and may lead to the development of new therapies.
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Affiliation(s)
- Mathias Ziersch
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| | - Dominik Harms
- Department of Infectious Diseases, Division of Viral Gastroenteritis and Hepatitis Pathogens and Enterovirus, Robert Koch Institute, 13353 Berlin, Germany
| | - Lena Neumair
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| | - Anke Kurreck
- Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
- BioNukleo GmbH, Ackerstrasse 76, 13355 Berlin, Germany
| | - Reimar Johne
- Department of Biological Safety, German Federal Institute for Risk Assessment, 12277 Berlin, Germany
| | - C-Thomas Bock
- Department of Infectious Diseases, Division of Viral Gastroenteritis and Hepatitis Pathogens and Enterovirus, Robert Koch Institute, 13353 Berlin, Germany
| | - Jens Kurreck
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
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Kanda T, Li TC, Takahashi M, Nagashima S, Primadharsini PP, Kunita S, Sasaki-Tanaka R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Suzuki R, Ishii K, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis E virus research and the Japanese clinical practice guidelines for hepatitis E virus infection. Hepatol Res 2024; 54:1-30. [PMID: 38874115 DOI: 10.1111/hepr.14062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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7
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Shahini E, Argentiero A, Andriano A, Losito F, Maida M, Facciorusso A, Cozzolongo R, Villa E. Hepatitis E Virus: What More Do We Need to Know? MEDICINA (KAUNAS, LITHUANIA) 2024; 60:998. [PMID: 38929615 PMCID: PMC11205503 DOI: 10.3390/medicina60060998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024]
Abstract
Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | | | - Alessandro Andriano
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, 70124 Bari, Italy;
| | - Francesco Losito
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | - Marcello Maida
- Gastroenterology and Endoscopy Unit, S. Elia-Raimondi Hospital, 93100 Caltanissetta, Italy;
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy; (F.L.); (R.C.)
| | - Erica Villa
- Gastroenterology Unit, CHIMOMO Department, University of Modena & Reggio Emilia, Via del Pozzo 71, 41121 Modena, Italy
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Zahmanova G, Takova K, Tonova V, Koynarski T, Lukov LL, Minkov I, Pishmisheva M, Kotsev S, Tsachev I, Baymakova M, Andonov AP. The Re-Emergence of Hepatitis E Virus in Europe and Vaccine Development. Viruses 2023; 15:1558. [PMID: 37515244 PMCID: PMC10383931 DOI: 10.3390/v15071558] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/11/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. Transmission of HEV mainly occurs via the fecal-oral route (ingesting contaminated water or food) or by contact with infected animals and their raw meat products. Some animals, such as pigs, wild boars, sheep, goats, rabbits, camels, rats, etc., are natural reservoirs of HEV, which places people in close contact with them at increased risk of HEV disease. Although hepatitis E is a self-limiting infection, it could also lead to severe illness, particularly among pregnant women, or chronic infection in immunocompromised people. A growing number of studies point out that HEV can be classified as a re-emerging virus in developed countries. Preventative efforts are needed to reduce the incidence of acute and chronic hepatitis E in non-endemic and endemic countries. There is a recombinant HEV vaccine, but it is approved for use and commercially available only in China and Pakistan. However, further studies are needed to demonstrate the necessity of applying a preventive vaccine and to create conditions for reducing the spread of HEV. This review emphasizes the hepatitis E virus and its importance for public health in Europe, the methods of virus transmission and treatment, and summarizes the latest studies on HEV vaccine development.
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Affiliation(s)
- Gergana Zahmanova
- Department of Plant Physiology and Molecular Biology, University of Plovdiv, 4000 Plovdiv, Bulgaria
- Department of Technology Transfer and IP Management, Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria
| | - Katerina Takova
- Department of Plant Physiology and Molecular Biology, University of Plovdiv, 4000 Plovdiv, Bulgaria
| | - Valeria Tonova
- Department of Plant Physiology and Molecular Biology, University of Plovdiv, 4000 Plovdiv, Bulgaria
| | - Tsvetoslav Koynarski
- Department of Animal Genetics, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
| | - Laura L Lukov
- Faculty of Sciences, Brigham Young University-Hawaii, Laie, HI 96762, USA
| | - Ivan Minkov
- Department of Technology Transfer and IP Management, Center of Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria
- Institute of Molecular Biology and Biotechnologies, 4108 Markovo, Bulgaria
| | - Maria Pishmisheva
- Department of Infectious Diseases, Pazardzhik Multiprofile Hospital for Active Treatment, 4400 Pazardzhik, Bulgaria
| | - Stanislav Kotsev
- Department of Infectious Diseases, Pazardzhik Multiprofile Hospital for Active Treatment, 4400 Pazardzhik, Bulgaria
| | - Ilia Tsachev
- Department of Microbiology, Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, Trakia University, 6000 Stara Zagora, Bulgaria
| | - Magdalena Baymakova
- Department of Infectious Diseases, Military Medical Academy, 1606 Sofia, Bulgaria
| | - Anton P Andonov
- Department of Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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9
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Gabrielli F, Alberti F, Russo C, Cursaro C, Seferi H, Margotti M, Andreone P. Treatment Options for Hepatitis A and E: A Non-Systematic Review. Viruses 2023; 15:v15051080. [PMID: 37243166 DOI: 10.3390/v15051080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/27/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal-oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.
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Affiliation(s)
- Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Francesco Alberti
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Cristina Russo
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Hajrie Seferi
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Marzia Margotti
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
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10
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Zhang F, Xu LD, Zhang Q, Wang A, Yu X, Liu S, Chen C, Wu S, Jin J, Lin A, Neculai D, Zhao B, Feng XH, Liang T, Xu P, Huang YW. Targeting proteostasis of the HEV replicase to combat infection in preclinical models. J Hepatol 2023; 78:704-716. [PMID: 36574921 DOI: 10.1016/j.jhep.2022.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 11/15/2022] [Accepted: 12/06/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action. METHODS Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase. RESULTS We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage. CONCLUSIONS In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals. IMPACT AND IMPLICATIONS Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development.
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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; 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; Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Qian 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; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Ailian Wang
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xinyuan Yu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Shengduo Liu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Department of Veterinary Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Chu Chen
- Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center (ZJU-HIC), Hangzhou, 310058, China; Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, 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
| | - Jianping Jin
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Aifu Lin
- MOE Laboratory of Biosystems Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Dante Neculai
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Bin Zhao
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xin-Hua Feng
- 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
| | - Tingbo Liang
- 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; Cancer Center, Zhejiang University, Hangzhou, 310058, 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; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Department of Veterinary Medicine, Zhejiang University, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China.
| | - Yao-Wei Huang
- Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center (ZJU-HIC), Hangzhou, 310058, China; Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
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11
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Cancela F, Rendon-Marin S, Quintero-Gil C, Houston DR, Gumbis G, Panzera Y, Pérez R, Arbiza J, Mirazo S. Modelling of Hepatitis E virus RNA-dependent RNA polymerase genotype 3 from a chronic patient and in silico interaction analysis by molecular docking with Ribavirin. J Biomol Struct Dyn 2023; 41:705-721. [PMID: 34861797 DOI: 10.1080/07391102.2021.2011416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatitis E Virus (HEV) infection is an emergent zoonotic disease, where chronic hepatitis E associated to solid organ transplant (SOT) recipients, related to genotype 3, is the clinical manifestation of major concern. In this setting, ribavirin (RBV) treatment is the only available therapy, though drug-resistant variants could emerge leading to a therapeutic failure. Crystallographic structures have not been reported for most of the HEV proteins, including the RNA-polymerase (RdRp). Therefore, the mechanism of action of RBV against HEV and the molecular interactions between this drug and RdRp are largely unknown. In this work, we aimed to model in silico the 3 D structure of a novel HEV3 RdRp (HEV_C1_Uy) from a chronically HEV infected-SOT recipient treated with RBV and to perform a molecular docking simulation between RBV triphosphate (RBVT), 7-methyl-guanosine-5'-triphosphate and the modelled protein. The models were generated using I-TASSER server and validated with multiple bioinformatics tools. The docking analysis were carried out with AutoDock Vina and LeDock software. We obtained a suitable model for HEV_C1_Uy (C-Score=-1.33, RMSD = 10.4 ± 4.6 Å). RBVT displayed a binding affinity of -7.6 ± 0.2 Kcal/mol by molecular docking, mediated by 6 hydrogen-bonds (Q195-O14, S198-O11, E257-O13, S260-O2, O3, S311-O11) between the finger's-palm-domains and a free binding energy of 31.26 ± 16.81 kcal/mol by molecular dynamics simulations. We identified the possible HEV RdRp interacting region for incoming nucleotides or analogs and provide novel insights that will contribute to better understand the molecular interactions of RBV and the enzyme and the mechanism of action of this antiviral drug.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Florencia Cancela
- Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Santiago Rendon-Marin
- Grupo de Investigación en Ciencias Animales - GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, sede Bucaramanga, Bucaramanga, Colombia
| | - Carolina Quintero-Gil
- Grupo de Investigación en Ciencias Animales - GRICA, Facultad de Medicina Veterinaria y Zootecnia, Universidad Cooperativa de Colombia, sede Bucaramanga, Bucaramanga, Colombia
| | - Douglas R Houston
- Institute of Quantitative Biology, Biochemistry and Biotechnology, The University of Edinburgh, Edinburgh, UK
| | - Gediminas Gumbis
- Institute of Quantitative Biology, Biochemistry and Biotechnology, The University of Edinburgh, Edinburgh, UK
| | - Yanina Panzera
- Sección Genética Evolutiva, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Ruben Pérez
- Sección Genética Evolutiva, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Juan Arbiza
- Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
| | - Santiago Mirazo
- Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.,Departamento de Bacteriología y Virología, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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12
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Hui W, Wei L. Treatment of Hepatitis E. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:215-226. [PMID: 37223869 DOI: 10.1007/978-981-99-1304-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) infections are the most common cause of acute hepatitis, but they can also take a chronic course. There is no specific therapy for acute hepatitis, and current treatment is supportive. Choosing ribavirin as the first-line therapy for chronic HEV is advisable, especially immunosuppressed individuals. Moreover, ribavirin therapy in the acute phase of infection provides major benefits for those at high risk of acute liver failure (ALF)/acute-on-chronic liver failure (ACLF). Pegylated interferon α has been used successfully for treatment of hepatitis E but is associated with major side effects. Cholestasis is one of the most common, but devastating, manifestations in hepatitis E. Current therapy for HEV aims to treat symptoms. Therapy generally involves several measures, such as vitamins, albumin, and plasma for supporting treatment, symptomatic treatment for cutaneous pruritus, ursodeoxycholic acid, Obeticholic acid, S-adenosylmethionine, etc. for removing jaundice. HEV infection during pregnancy and patients with underlying liver disease may develop liver failure. For these patients, active monitoring, standard care, and supportive treatment are the foundations. Ribavirin has successfully been used to prevent liver transplantation (LT). Prevention and treatment of complications are important for treatment of liver failure. Liver support devices are intended to support liver function until such time as native liver function recovers, or until LT. LT is widely considered as irreplaceable and definitive treatment for liver failure, particularly for patients who do not improve with supportive measures to sustain life.
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Affiliation(s)
- Wei Hui
- Chronic Disease Management Center, Youan Hospital, Capital Medical University, Beijing, China
| | - Linlin Wei
- The Second Department of Liver Disease Center, Youan Hospital, Capital Medical University, Beijing, China.
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13
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Gupta J, Irfan M, Ramgir N, Muthe KP, Debnath AK, Ansari S, Gandhi J, Ranjith-Kumar CT, Surjit M. Antiviral Activity of Zinc Oxide Nanoparticles and Tetrapods Against the Hepatitis E and Hepatitis C Viruses. Front Microbiol 2022; 13:881595. [PMID: 35814711 PMCID: PMC9260229 DOI: 10.3389/fmicb.2022.881595] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/17/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis. The disease takes a severe form in pregnant women, leading to around 30% mortality. Zinc is an essential micronutrient that plays a crucial role in multiple cellular processes. Our earlier findings demonstrated the antiviral activity of zinc salts against HEV infection. Zinc oxide (ZnO) and its nanostructures have attracted marked interest due to their unique characteristics. Here we synthesized ZnO nanoparticles [ZnO(NP)] and tetrapod-shaped ZnO nanoparticles [ZnO(TP)] and evaluated their antiviral activity. Both ZnO(NP) and ZnO(TP) displayed potent antiviral activity against hepatitis E and hepatitis C viruses, with the latter being more effective. Measurement of cell viability and intracellular reactive oxygen species levels revealed that both ZnO(NP) and ZnO(TP) are noncytotoxic to the cells even at significantly higher doses, compared to a conventional zinc salt (ZnSO4). Our study paves the way for evaluation of the potential therapeutic benefit of ZnO(TP) against HEV and HCV.
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Affiliation(s)
- Jyoti Gupta
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Minnah Irfan
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Niranjan Ramgir
- Technical Physics Division, Bhabha Atomic Research Center, Mumbai, India
| | - K. P. Muthe
- Technical Physics Division, Bhabha Atomic Research Center, Mumbai, India
| | - A. K. Debnath
- Technical Physics Division, Bhabha Atomic Research Center, Mumbai, India
| | - Shabnam Ansari
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Jaya Gandhi
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - C. T. Ranjith-Kumar
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Milan Surjit
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
- *Correspondence: Milan Surjit
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14
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Wasuwanich P, Sirisreetreerux P, Ingviya T, Kraus ES, Brennan DC, Sue PK, Jackson AM, Oshima K, Philosophe B, Montgomery RA, Karnsakul W. Hepatitis E virus infection and rejection in kidney transplant recipients. Transpl Immunol 2021; 70:101517. [PMID: 34923120 DOI: 10.1016/j.trim.2021.101517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/10/2021] [Accepted: 12/12/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection has been associated with immune-mediated kidney diseases in developing countries. However, its relationship with kidney transplant outcomes has never been studied. We investigated the association between HEV infection and kidney graft rejection among kidney transplant recipients (KTRs). METHODS We conducted a matched cohort and longitudinal study utilizing banked sera following kidney transplantation during 1988-2012. Studies with evidence of post-transplantation HEV infection were identified by positive ELISA tests (anti-HEV IgM or anti-HEV IgG seroconversion) or positive HEV PCR and matched to KTR controls with negative HEV ELISA and PCR tests in a 1:5 ratio by age, sex, crossmatch status, immunosuppression era, and time of HEV testing. Outcome data collected included time to first kidney graft rejection, transaminases, and glomerular filtration rates. Log-ranked test was used to analyze survival. RESULTS Of 271 KTRs, 9 (3%) had evidence of post-transplantation HEV infection and were compared to 45 negative, matched controls. Median age at transplantation was 46 years. Kidney graft rejection was reported in 8 (89%) of cases and 21 (47%) of controls. Median time to first episode of kidney graft rejection was 17.4 months in cases and 30.8 months in controls (p = 0.029), with a higher hazard of developing kidney graft rejection in cases (HR = 3.23, 95% CI: 1.19-8.79). Lower mean glomerular filtration rates over time were observed in cases (35 mL/min/1.73m2) versus controls (42.4 mL/min/1.73m2) but did not reach significance (p = 0.24). CONCLUSION Subjects with evidence of post-transplantation HEV infection demonstrated earlier kidney graft rejection compared to controls.
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Affiliation(s)
- Paul Wasuwanich
- Division of Pediatric Gastroenterology, Nutrition, and Hepatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Thammasin Ingviya
- Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Family and Preventive Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Edward S Kraus
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel C Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Paul K Sue
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Annette M Jackson
- Departments of Surgery and Immunology, Duke University, Durham, NC, USA
| | - Kiyoko Oshima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Benjamin Philosophe
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A Montgomery
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; NYU Langone Transplant Institute, New York University Langone Health, New York, NY, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Nutrition, and Hepatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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15
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Lhomme S, Abravanel F, Cintas P, Izopet J. Hepatitis E Virus Infection: Neurological Manifestations and Pathophysiology. Pathogens 2021; 10:pathogens10121582. [PMID: 34959537 PMCID: PMC8705630 DOI: 10.3390/pathogens10121582] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) is the first cause of viral hepatitis in the world. While the water-borne HEV genotypes 1 and 2 are found in developing countries, HEV genotypes 3 and 4 are endemic in developed countries due to the existence of animal reservoirs, especially swine. An HEV infection produces many extra-hepatic manifestations in addition to liver symptoms, especially neurological disorders. The most common are neuralgic amyotrophy or Parsonage–Turner syndrome, Guillain–Barré syndrome, myelitis, and encephalitis. The pathophysiology of the neurological injuries due to HEV remains uncertain. The immune response to the virus probably plays a role, but direct virus neurotropism could also contribute to the pathophysiology. This review describes the main neurological manifestations and their possible pathogenic mechanisms.
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Affiliation(s)
- Sébastien Lhomme
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31300 Toulouse, France; (F.A.); (J.I.)
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France
- Correspondence: ; Tel.: +33-(0)-5-67-69-04-24
| | - Florence Abravanel
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31300 Toulouse, France; (F.A.); (J.I.)
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France
| | - Pascal Cintas
- Service de Neurologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France;
| | - Jacques Izopet
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31300 Toulouse, France; (F.A.); (J.I.)
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France
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El Kassas M, Alboraie M, El-Sayed M, Elbehiry S, Sherief A, Youssef M, Moaz I, El Tahan A, Abdeen N, Eysa B, Aziz AA, Tawheed A, Ezzat S, Hassany M. Effect of disease stage and treatment outcomes on the dynamics of liver functions during and after treatment of hepatitis C with directly acting antivirals. Eur J Gastroenterol Hepatol 2021; 33:e302-e307. [PMID: 34080825 DOI: 10.1097/meg.0000000000002043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Virus C infection is recently treated successfully with plenty of direct antiviral agents (DAAs). We aimed to evaluate the effect of disease stage and treatment outcome on the dynamics of liver functions during treatment of hepatitis C with DAAs. METHODS We reported the liver function in 2354 subjects diagnosed as chronic hepatitis C before, during and after treatment with different DAAs regimens. Patients were classified into two groups according to treatment response with further subclassification according to the presence or absence of cirrhosis, and changes in liver functions were compared in each group and subgroup. RESULTS Totally 2213 (94%) achieved sustained virological response (SVR) to DAAs therapy with significant improvement in all liver biochemistry. Also, there was an improvement in the non-SVR group's liver enzymes in relapsers during and after treatment; however, there was no improvement in serum albumin. We noticed a slight increase in serum bilirubin at weeks 4 and 8 for both groups. CONCLUSION DAAs therapy is associated with improvement of the liver biochemical profile and improved outcome in the majority of chronic hepatitis C virus patients due to suppression of viral replication. However, the long-term impact of DAAs therapy needs to be further evaluated.
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Affiliation(s)
| | | | | | | | - Ahmed Sherief
- Tropical Medicine Department, Faculty of Medicine Ain Shams University, Cairo
| | | | - Inas Moaz
- Epidemiology and Preventive Medicine Department, National Liver Institute, Menoufia University, Menoufia
| | - Adel El Tahan
- New Cairo Viral Hepatitis, Treatment Unit, New Cairo Hospital, Cairo
| | - Nermeen Abdeen
- Tropical Medicine, Faculty of Medicine, Alexandria University, Alexandria
| | - Basem Eysa
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute
| | - Ayman A Aziz
- Gastroenterology and Hepatology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Ahmed Tawheed
- Endemic Medicine Department, Faculty of Medicine, Helwan University
| | - Sameera Ezzat
- Epidemiology and Preventive Medicine Department, National Liver Institute, Menoufia University, Menoufia
| | - Mohamed Hassany
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute
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17
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Kamani L, Padhani ZA, Das JK. Hepatitis E: Genotypes, strategies to prevent and manage, and the existing knowledge gaps. JGH Open 2021; 5:1127-1134. [PMID: 34621997 PMCID: PMC8485408 DOI: 10.1002/jgh3.12646] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 08/02/2021] [Accepted: 08/14/2021] [Indexed: 12/23/2022]
Abstract
Hepatitis E virus (HEV) is considered an emergent source of viral hepatitis worldwide, with an increasing burden of jaundice, liver failure, extrahepatic illnesses, and deaths in developed countries. With the scarcity of data from efficient animal models, there are still open-ended questions about designing new models to study pathogenesis, types, virology, and evolution of these viruses. With an emphasis on available data and updates, there is still enough information to understand the HEV life cycle, pathogen interaction with the host, and the valuation of the role of vaccine and new anti-HEV therapies. However, the World Health Organization (WHO) and the European Association for the Study of the Liver (EASL) preferred to stress prevention and control measures of HEV infections in animals, zoonotic transmission, and foodborne transmission. It is being reviewed that with current knowledge on HEV and existing prevention tools, there is an excellent room for in-depth information about the virus strains, their replication, pathogenicity, and virulence. The current knowledge set also has gaps regarding standardized and validated diagnostic tools, efficacy and safety of the vaccine, and extrahepatic manifestations specifically in pregnant females, immunocompromised patients, and others. This review highlights the areas for more research exploration, focusing on enlisted research questions based on HEV infection to endorse the need for significant improvement in the current set of knowledge for this public health problem.
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Affiliation(s)
- Lubna Kamani
- Associate Professor & Director, GI Residency Program, Department of GastroenterologyLiaquat National Hospital and Medical CollegeKarachiPakistan
- ConsultantAga Khan University HospitalKarachiPakistan
| | - Zahra Ali Padhani
- Health Policy and Management, Manager (Research)Aga Khan University HospitalKarachiPakistan
| | - Jai K Das
- Assistant Professor and Head, Section of Public Health and EpidemiologyAga Khan University HospitalKarachiPakistan
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18
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Tripathi A, Banerjee A, Vrati S. Development and characterization of an animal model of Japanese encephalitis virus infection in adolescent C57BL/6 mouse. Dis Model Mech 2021; 14:dmm049176. [PMID: 34447981 PMCID: PMC8543065 DOI: 10.1242/dmm.049176] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/20/2021] [Indexed: 12/28/2022] Open
Abstract
A mouse-adapted isolate of Japanese encephalitis virus (JEV), designated as JEV-S3, was generated by serially passaging the P20778 strain of the virus in 3- to 4-week-old C57BL/6 mice. Blood-brain barrier leakage was evident in JEV-S3-infected mice, in which viral antigens and RNA were consistently demonstrated in the brain, along with infiltration of activated immune cells, as evidenced by an increased CD45+CD11b+ cell population. Histopathology studies showed the presence of perivascular cuffing, haemorrhage and necrotic foci in the virus-infected brain, conforming to the pathological changes seen in the brain of JEV-infected patients. Mass spectrometry studies characterized the molecular events leading to brain inflammation in the infected mice. Notably, a significant induction of inflammatory cytokines, such as IFNγ, IL6, TNFα and TGFβ, was observed. Further, genome sequencing of the JEV-S3 isolate identified the mutations selected during the mouse passage of the virus. Overall, we present an in-depth characterization of a robust and reproducible mouse model of JEV infection. The JEV-S3 isolate will be a useful tool to screen antivirals and study virus pathogenesis in the adolescent mouse model.
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MESH Headings
- Adaptation, Physiological
- Aging/pathology
- Amino Acid Substitution
- Animals
- Antiviral Agents/pharmacology
- Astrocytes/drug effects
- Astrocytes/pathology
- Blood-Brain Barrier/drug effects
- Blood-Brain Barrier/pathology
- Caspases/metabolism
- Cell Line
- Disease Models, Animal
- Encephalitis Virus, Japanese/genetics
- Encephalitis Virus, Japanese/pathogenicity
- Encephalitis Virus, Japanese/physiology
- Encephalitis, Japanese/complications
- Encephalitis, Japanese/genetics
- Encephalitis, Japanese/pathology
- Encephalitis, Japanese/virology
- Gene Expression Regulation/drug effects
- Genome, Viral
- Inflammation/complications
- Inflammation/pathology
- Interferons/pharmacology
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Microglia/drug effects
- Microglia/pathology
- Mutation/genetics
- Virulence/drug effects
- Virus Replication/drug effects
- Virus Replication/physiology
- Mice
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Affiliation(s)
- Aarti Tripathi
- Infection and Immunology, Translational Health Science and Technology Institute, Faridabad 121001, India
| | - Arup Banerjee
- Infection and Immunology, Translational Health Science and Technology Institute, Faridabad 121001, India
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India
| | - Sudhanshu Vrati
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India
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19
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Kupke P, Werner JM. Hepatitis E Virus Infection-Immune Responses to an Underestimated Global Threat. Cells 2021; 10:cells10092281. [PMID: 34571931 PMCID: PMC8468229 DOI: 10.3390/cells10092281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat.
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20
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Glitscher M, Hildt E. Hepatitis E virus egress and beyond - the manifold roles of the viral ORF3 protein. Cell Microbiol 2021; 23:e13379. [PMID: 34272798 DOI: 10.1111/cmi.13379] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/18/2021] [Accepted: 07/06/2021] [Indexed: 11/30/2022]
Abstract
Although the hepatitis E virus represents an uprising threat to the global community by representing the commonest cause of an acute viral hepatitis worldwide, its life cycle is grossly understudied. Albeit HEV is a non-enveloped virus, its progeny is released as quasi-enveloped virions. Thus, the responsible accessory protein pORF3 gained rising attention in the past years. It mediates viral release via the exosomal route by targeting the viral capsid to the endosomal system, more precisely to multivesicular bodies. As this is followed by quasi-envelopment, pORF3 may in terms represent a substitute to a conventional envelope protein. This feature proofs to be rather unique with respect to other enteric viruses, although the protein's role in the viral life cycle seems to reach far beyond simply maintaining release of progeny viruses. How pORF3 affects viral morphogenesis, how it mediates efficient viral release and how it supports viral spread is summarised in this microreview. With this, we aim to shed light on functions of pORF3 to gain further insights in still enigmatic aspects of the HEV life cycle. TAKE AWAYS: HEV is released as exosome via multivesicular bodies Viral pORF3 mediates release via endosomal complexes required for transport pORF3 modulates various cellular processes in infected cells Elucidation of pORF3-related processes imply novel clinical strategies.
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Affiliation(s)
| | - Eberhard Hildt
- Department Virology, Paul-Ehrlich-Institut, Langen, Germany
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21
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Velavan TP, Pallerla SR, Johne R, Todt D, Steinmann E, Schemmerer M, Wenzel JJ, Hofmann J, Shih JWK, Wedemeyer H, Bock CT. Hepatitis E: An update on One Health and clinical medicine. Liver Int 2021; 41:1462-1473. [PMID: 33960603 DOI: 10.1111/liv.14912] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 03/09/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022]
Abstract
The hepatitis E virus (HEV) is one of the main causes of acute hepatitis and the de facto global burden is underestimated. HEV-related clinical complications are often undetected and are not considered in the differential diagnosis. Convincing findings from studies suggest that HEV is clinically relevant not only in developing countries but also in industrialized countries. Eight HEV genotypes (HEV-1 to HEV-8) with different human and animal hosts and other HEV-related viruses are in circulation. Transmission routes vary by genotype and location, with large waterborne outbreaks in developing countries and zoonotic food-borne infections in developed countries. An acute infection can be aggravated in pregnant women, organ transplant recipients, patients with pre-existing liver disease and immunosuppressed patients. HEV during pregnancy affects the fetus and newborn with an increased risk of vertical transmission, preterm and stillbirth, neonatal jaundice and miscarriage. Hepatitis E is associated with extrahepatic manifestations that include neurological disorders such as neuralgic amyotrophy, Guillain-Barré syndrome and encephalitis, renal injury and haematological disorders. The risk of transfusion-transmitted HEV is increasingly recognized in Western countries where the risk may be because of a zoonosis. RNA testing of blood components is essential to determine the risk of transfusion-transmitted HEV. There are currently no approved drugs or vaccines for HEV infections. This review focuses on updating the latest developments in zoonoses, screening and diagnostics, drugs in use and under development, and vaccines.
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Affiliation(s)
- Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam.,Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
| | - Srinivas R Pallerla
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam
| | - Reimar Johne
- German Federal Institute for Risk Assessment, Berlin, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mathias Schemmerer
- Institute of Clinical Microbiology and Hygiene, National Consultant Laboratory for HAV and HEV, University Medical Center Regensburg, Regensburg, Germany
| | - Jürgen J Wenzel
- Institute of Clinical Microbiology and Hygiene, National Consultant Laboratory for HAV and HEV, University Medical Center Regensburg, Regensburg, Germany
| | - Jörg Hofmann
- Institute of Virology, Charité Universitätsmedizin Berlin, Labor Berlin-Charité-Vivantes GmbH, Berlin, Germany
| | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Partner Hannover-Braunschweig, Braunschweig, Germany
| | - Claus-Thomas Bock
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
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22
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Ji H, Chen S, He Q, Wang W, Gong S, Qian Z, Zhang Y, Wei D, Yu W, Huang F. The different replication between nonenveloped and quasi-enveloped hepatitis E virus. J Med Virol 2021; 93:6267-6277. [PMID: 34076903 DOI: 10.1002/jmv.27121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 12/15/2022]
Abstract
Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. However, the understanding of the HEV life cycle is limited. In the present study, cells were separately infected with nonenveloped HEV (derived from feces or bile) or quasi-enveloped HEV (derived from the cell culture after serial passages, eHEV) and observed by confocal fluorescence microscopy to investigate the life cycle of HEV. HEV finished its binding and entry into host cells at first 6 h postinoculation (hpi). Cells inoculated with eHEV showed less infectivity than cells inoculated with nonenveloped HEV. Newly synthesized progeny virions were released into the supernatant of cell cultures from 48 hpi. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis results showed that the supernatant's progeny viruses were infectious even after five serial passages. These results show the significant difference between nonenveloped HEV and eHEV, which will provide novel insights into the HEV replication cycle. The efficient cell culture of HEV will promote the development of anti-HEV drugs and vaccines.
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Affiliation(s)
- Hanbin Ji
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Shuangfeng Chen
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Qiuxia He
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wenjing Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Shilin Gong
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Zhongyao Qian
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Yike Zhang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Daqiao Wei
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, PR China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, PR China.,Yunnan Provincial Key Laboratory of Clinical Virology, Kunming, PR China
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23
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Kamar N, Abravanel F, Behrendt P, Hofmann J, Pageaux GP, Barbet C, Moal V, Couzi L, Horvatits T, De Man RA, Cassuto E, Elsharkawy AM, Riezebos-Brilman A, Scemla A, Hillaire S, Donnelly MC, Radenne S, Sayegh J, Garrouste C, Dumortier J, Glowaki F, Matignon M, Coilly A, Figueres L, Mousson C, Minello A, Dharancy S, Rerolle JP, Lebray P, Etienne I, Perrin P, Choi M, Marion O, Izopet J, Cointault O, Del Bello A, Espostio L, Hebral AL, Lavayssière L, Lhomme S, Mansuy JM, Wedemeyer H, Nickel P, Bismuth M, Stefic K, Büchler M, D’Alteroche L, Colson P, Bufton S, Ramière C, Trimoulet P, Pischke S, Todesco E, Sberro Soussan R, Legendre C, Mallet V, Johannessen I, Simpson K. Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study. Clin Infect Dis 2021; 71:1204-1211. [PMID: 31793638 DOI: 10.1093/cid/ciz953] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 10/01/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. METHODS Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months. RESULTS After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. CONCLUSIONS This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, Centre Hospitalier Universitaire (CHU) Rangueil, Institut National de la Santé et de la Recherche Médicale (INSERM) U1043, Institut Fédératif de Recherche Bio-médicale de Toulouse (IFR-BMT), University Paul Sabatier, Toulouse, France
| | - Florence Abravanel
- Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, and Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, German Centre for Infection Research, Hannover, Germany
| | - Jörg Hofmann
- Charité Universitätsmedizin Berlin, Department of Nephrology and Intensive Care and Institute of Virology, Labor Berlin Charité-Vivantes-GmbH, Berlin, Germany
| | | | - Christelle Barbet
- Department of Nephrology and Clinical Immunology, Bretonneau Hospital, University Hospital, Tours, France
| | - Valérie Moal
- Aix Marseille Université, Asistance Publique Hôpitaux de Marseille, Institut Pour la Recherche Pour le Développement, Microbes, Evolution, Phylogénie et Infection, Institut Hospitalo-Universitaire-Méditerranée Infection, Hôpital Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | - Lionel Couzi
- Department of Nephrology and Transplantation, CHU Bordeaux, Bordeaux, France
| | - Thomas Horvatits
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Robert A De Man
- Departments of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | | - Annelies Riezebos-Brilman
- Department of Medical Microbiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Anne Scemla
- Service de néphrologie-transplantation, Hôpital Necker, Assitance publique- Hôpitaux de Paris (AP-HP), Paris et Université Paris Descartes, Paris, France
| | | | - Mhairi C Donnelly
- Department of Hepatology and Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Sylvie Radenne
- Department of Hepatology and Liver Transplantation, CHU de la Croix Rousse, Lyon, France
| | - Johnny Sayegh
- Department of Nephrology and Transplantation, CHU Angers, Angers, France
| | - Cyril Garrouste
- Department of Nephrology, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Jérôme Dumortier
- Department of Hepatology, Edouard Herriot Hospital, CHU Lyon, Lyon, France
| | | | - Marie Matignon
- Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Equipe 21, INSERM U 955, Créteil, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, INSERM U1193, Université Paris-Sud Paris-Saclay, Villejuif, France
| | - Lucile Figueres
- Department of Nephrology and Clinical Immunology, CHU Nantes, Nantes, France
| | | | - Anne Minello
- Department of Hepatogastroenterology and Digestive Oncology, CHU François Mitterrand, Dijon, France
| | - Sébastien Dharancy
- Hôpital Claude Huriez, Services Maladies de l'Appareil Digestif, INSERM Unité 995, Lille, France
| | | | - Pascal Lebray
- Department of Hepatology, Pitié Salpétrière Hospital, Paris, France
| | | | - Peggy Perrin
- Department of Nephrology, CHU Strasbourg, Strasbourg, France
| | - Mira Choi
- Charité Universitätsmedizin Berlin, Department of Nephrology and Intensive Care and Institute of Virology, Labor Berlin Charité-Vivantes-GmbH, Berlin, Germany
| | - Olivier Marion
- Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France
| | - Jacques Izopet
- Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France
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24
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Geraghty RJ, Aliota MT, Bonnac LF. Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses 2021; 13:667. [PMID: 33924302 PMCID: PMC8069527 DOI: 10.3390/v13040667] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 01/18/2023] Open
Abstract
The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.
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Affiliation(s)
- Robert J. Geraghty
- Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Matthew T. Aliota
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA;
| | - Laurent F. Bonnac
- Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA;
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25
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Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol 2021; 27:1240-1254. [PMID: 33828397 PMCID: PMC8006097 DOI: 10.3748/wjg.v27.i12.1240] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/17/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is underdiagnosed due to the use of serological assays with low sensitivity. Although most patients with HEV recover completely, HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.
AIM To demonstrate the prevalence of HEV infection in solid organ transplant (SOT) recipients.
METHODS We searched Ovid MEDLINE, EMBASE, and the Cochrane Library for eligible articles through October 2020. The inclusion criteria consisted of adult patients with history of SOT. HEV infection is confirmed by either HEV-immunoglobulin G, HEV-immunoglobulin M, or HEV RNA assay.
RESULTS Of 563 citations, a total of 22 studies (n = 4557) were included in this meta-analysis. The pooled estimated prevalence of HEV infection in SOT patients was 20.2% [95% confidence interval (CI): 14.9-26.8]. The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver (27.2%; 95%CI: 20.0-35.8), kidney (12.8%; 95%CI: 9.3-17.3), heart (12.8%; 95%CI: 9.3-17.3), and lung (5.6%; 95%CI: 1.6-17.9). Comparison across organ transplants demonstrated statistical significance (Q = 16.721, P = 0.002). The subgroup analyses showed that the prevalence of HEV infection among SOT recipients was significantly higher in middle-income countries compared to high-income countries. The pooled estimated prevalence of de novo HEV infection was 5.1% (95%CI: 2.6-9.6) and the pooled estimated prevalence of acute HEV infection was 4.3% (95%CI: 1.9-9.4).
CONCLUSION HEV infection is common in SOT recipients, particularly in middle-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants. More studies examining the clinical impacts of HEV infection in SOT recipients, such as graft failure, rejection, and mortality are warranted.
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Affiliation(s)
- Panupong Hansrivijit
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | - Angkawipa Trongtorsak
- Department of Internal Medicine, Amita Health Saint Francis Hospital, Evanston, IL 60202, United States
| | - Max M Puthenpura
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, United States
| | - Boonphiphop Boonpheng
- David Geffen School of Medicine, University of California, Los Angeles, Division of Nephrology, Los Angeles, CA 90095, United States
| | - Charat Thongprayoon
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Karn Wijarnpreecha
- Department of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, United States
| | - Avishek Choudhury
- School of Systems and Enterprises, Stevens Institute of Technology, Hoboken, NJ 07030, United States
| | - Wisit Kaewput
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok 10400, Thailand
| | - Shennen A Mao
- Department of Transplant Surgery, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Michael A Mao
- Department of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Caroline C Jadlowiec
- Department of Transplant Center, Mayo Clinic, Scottsdale, AZ 85259, United States
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26
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Gorris M, van der Lecq BM, van Erpecum KJ, de Bruijne J. Treatment for chronic hepatitis E virus infection: A systematic review and meta-analysis. J Viral Hepat 2021; 28:454-463. [PMID: 33301609 PMCID: PMC7898834 DOI: 10.1111/jvh.13456] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/09/2020] [Accepted: 11/23/2020] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection can cause chronic hepatitis in immunocompromised patients with significant chance of progressive fibrosis and possibly cirrhosis. The aim of this systematic review was to summarize the efficacy and safety of the various treatment options for chronic hepatitis E. We performed a systematic literature search. The primary outcome measure was a sustained virological response (SVR). Secondary end points were rapid virological response (RVR), relapse rates, side effects and adverse events. Forty-four articles were included with a total of 582 patients. Reduction of immunosuppressive medication induced viral clearance in 55/174 (32%) of the patients. Meta-analysis of 395 patients showed a pooled SVR rate of 78% (95-CI 72%-84%) after ribavirin treatment. Twenty-five per cent of the patients obtained a RVR, whereas a relapse occurred in 18% of the patients. Anaemia during treatment led to dose reduction, use of erythropoietin and/or blood transfusion in 37% of the patients. A second treatment attempt with ribavirin led to a SVR in 39/51 (76%) of the patients. Pegylated interferon-alpha was administered to 13 patients and SVR was obtained in 85%. Two patients (15%) suffered from acute transplant rejection during treatment with interferon. In conclusion, reduction of immunosuppressive medication and treatment with ribavirin is safe, generally well tolerated and induced viral clearance in 32% and 78% of patients, respectively. Therefore, ribavirin should be considered as first treatment step for chronic hepatitis E. Treatment with pegylated interferon-alpha increases the risk of transplant rejection and should therefore be administered with great caution.
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Affiliation(s)
- Myrte Gorris
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Bernice M. van der Lecq
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Karel J. van Erpecum
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Joep de Bruijne
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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27
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Belei O, Ancusa O, Mara A, Olariu L, Amaricai E, Folescu R, Zamfir CL, Gurgus D, Motoc AG, Stânga LC, Strat L, Marginean O. Current Paradigm of Hepatitis E Virus Among Pediatric and Adult Patients. Front Pediatr 2021; 9:721918. [PMID: 34660485 PMCID: PMC8515027 DOI: 10.3389/fped.2021.721918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/31/2021] [Indexed: 12/26/2022] Open
Abstract
Hepatitis E virus (HEV) infection is a polymorphic condition, present throughout the world and involving children and adults. Multiple studies over the last decade have contributed to a better understanding of the natural evolution of this infection in various population groups, several reservoirs and transmission routes being identified. To date, acute or chronic HEV-induced hepatitis has in some cases remained underdiagnosed due to the lower accuracy of serological tests and due to the evolutionary possibility with extrahepatic manifestations. Implementation of diagnostic tests based on nucleic acid analysis has increased the detection rate of this disease. The epidemiological and clinical features of HEV hepatitis differ depending on the geographical areas studied. HEV infection is usually a self-limiting condition in immunocompetent patients, but in certain categories of vulnerable patients it can induce a sudden evolution toward acute liver failure (pregnant women) or chronicity (immunosuppressed patients, post-transplant, hematological, or malignant diseases). In acute HEV infections in most cases supportive treatment is sufficient. In patients who develop chronic hepatitis with HEV, dose reduction of immunosuppressive medication should be the first therapeutic step, especially in patients with transplant. In case of unfavorable response, the initiation of antiviral therapy is recommended. In this review, the authors summarized the essential published data related to the epidemiological, clinical, paraclinical, and therapeutic aspects of HEV infection in adult and pediatric patients.
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Affiliation(s)
- Oana Belei
- First Pediatric Clinic, Disturbance of Growth and Development on Children Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Oana Ancusa
- Fifth Department of Internal Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Adelina Mara
- Department of Internal Medicine, Emergency City Hospital, Timisoara, Romania
| | - Laura Olariu
- First Pediatric Clinic, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Elena Amaricai
- Department of Rehabilitation Physical Medicine and Rheumatology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Roxana Folescu
- Department of Balneology, Medical Recovery and Rheumatology, Family Discipline, Center for Preventive Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Carmen Lacramioara Zamfir
- Department of Morpho-Functional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
| | - Daniela Gurgus
- Department of Balneology, Medical Recovery and Rheumatology, Family Discipline, Center for Preventive Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Andrei G Motoc
- Department of Anatomy and Embriology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Livia Claudia Stânga
- Department of Microbiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Liliana Strat
- Department of Mother and Child Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
| | - Otilia Marginean
- First Pediatric Clinic, Disturbance of Growth and Development on Children Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
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28
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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29
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Thakur V, Ratho RK, Kumar S, Saxena SK, Bora I, Thakur P. Viral Hepatitis E and Chronicity: A Growing Public Health Concern. Front Microbiol 2020; 11:577339. [PMID: 33133046 PMCID: PMC7550462 DOI: 10.3389/fmicb.2020.577339] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E viral infection recently emerges as a global health concern. Over the last decade, the understanding of hepatitis E virus (HEV) had changed with the discovery of new genotypes like genotype-7 and genotype-8 with associated host and mode of infection. Diversification in the mode of hepatitis E infection transmission through blood transfusion, and organ transplants in contrast to classical feco-oral and zoonotic mode is the recent medical concern. The wide spectrum of infection ranging from self-limiting to acute liver failure is now overpowered by HEV genotype-specific chronic infection especially in transplant patients. This concern is further escalated by the extra-hepatic manifestations of HEV targeting the central nervous system (CNS), kidney, heart, and pancreas. However, with the development of advanced efficient cell culture systems and animal models simulating the infection, much clarity toward understanding the pathogenetic mechanism of HEV has been developed. Also this facilitates the development of vaccines research or therapeutics. In this review, we highlight all the novel findings in every aspect of HEV with special emphasis on recently emerging chronic mode of infection with specific diagnosis and treatment regime with an optimistic hope to help virologists and/or liver specialists working in the field of viral hepatitis.
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Affiliation(s)
- Vikram Thakur
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Radha Kanta Ratho
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Swatantra Kumar
- Centre for Advanced Research, Faculty of Medicine, King George's Medical University, Lucknow, India
| | - Shailendra K Saxena
- Centre for Advanced Research, Faculty of Medicine, King George's Medical University, Lucknow, India
| | - Ishani Bora
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pryanka Thakur
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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30
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Nasir M, Wu GY. HEV and HBV Dual Infection: A Review. J Clin Transl Hepatol 2020; 8:313-321. [PMID: 33083255 PMCID: PMC7562801 DOI: 10.14218/jcth.2020.00030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/29/2020] [Accepted: 06/07/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis E virus (HEV) is a global health problem, affecting about 20 million people worldwide. There is significant overlap of hepatitis B virus (HBV) and HEV endemicity in many Asian countries where dual infections with HEV and HBV can occur. Though the clinical course of HEV is largely self-limited, HEV superinfection in patients with chronic hepatitis B (CHB) can result in acute exacerbation of underlying CHB. HEV superinfection in patients with CHB-related cirrhosis has been identified as a risk factor for decompensated cirrhosis and an independent predictor of mortality. Whereas acute HEV infection in pregnancy can cause fulminant liver failure, the few studies on pregnant patients with dual HBV and HEV infection have shown a subclinical course. Immunosuppression is a risk factor for the development of chronic HEV infection, which can be managed by decreasing the dose of immune-suppressants and administering ribavirin. Vaccination for HEV has been developed and is in use in China but its efficacy in patients with CHB has yet to be established in the USA. In this review, we appraise studies on dual infection with HEV and HBV, including the effect of HEV superinfection and coinfection in CHB, management strategies used and the role of active vaccination in the prevention of HEV.
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Affiliation(s)
- Myra Nasir
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Myra Nasir, Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. Tel: +1-860-470-6616, E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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31
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Crum-Cianflone NF. Therapy for Chronic Hepatitis E Virus Infection-Current Recommendations and Future Aspirations. Clin Infect Dis 2020; 71:1212-1214. [PMID: 31793631 DOI: 10.1093/cid/ciz955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 09/26/2019] [Indexed: 11/14/2022] Open
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32
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Hepatitis E virus infection in liver transplant recipients: a descriptive literature review. Eur J Gastroenterol Hepatol 2020; 32:916-922. [PMID: 32091436 DOI: 10.1097/meg.0000000000001682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection has been recognized as a rising hepatotropic viral infection in the developing countries but overlooked in the developed countries, due to its lower prevalence. However, hepatitis E virus prevalence is on rise in the liver transplant recipients due to immunosuppression, which needs prompt recognition by healthcare practitioners. Hepatitis E virus infection is commonly believed to be transmitted via an animal host; but in the post-liver transplant patients, it can also be acquired via blood and blood products transfusion and autochthonous route. Previous studies have shown the significance of hepatitis E virus infection in post-liver transplant, as the patients at a high risk of progressing to chronic hepatitis and cirrhosis. Pediatric patients are at higher risk of hepatitis E virus infection post-liver transplant. Specific hepatitis E virus genotypes have the potential for greater severity. The clinical manifestation of hepatitis E virus can also present as extrahepatic features which need high level of suspicion for early recognition and treatment. Treatment options of hepatitis E virus range from immunosuppressive drug minimization, ribavirin therapy to novel direct-acting antiviral regimens. Herein, we aim to explore epidemiology, prevalence, risk factor, diagnosis, and management of hepatitis E virus infection giving special attention to liver transplant recipients.
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33
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Harvala H, Hewitt PE, Reynolds C, Pearson C, Haywood B, Tettmar KI, Ushiro-Lumb I, Brailsford SR, Tedder R, Ijaz S. Hepatitis E virus in blood donors in England, 2016 to 2017: from selective to universal screening. ACTA ACUST UNITED AC 2020; 24. [PMID: 30862338 PMCID: PMC6415500 DOI: 10.2807/1560-7917.es.2019.24.10.1800386] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Introduction Hepatitis E virus (HEV), the most common cause of acute hepatitis in many European countries, is transmitted through consumption of processed pork but also via blood transfusion and transplantation. HEV infection can become persistent in immunocompromised individuals. Aim We aimed to determine the incidence and epidemiology of HEV infection in English blood donors since the introduction of donation screening in 2016. Methods Between March 2016 and December 2017, 1,838,747 blood donations were screened for HEV RNA. Donations containing HEV RNA were further tested for serological markers, RNA quantification and viral phylogeny. Demographics, travel and diet history were analysed for all infected donors. Results We identified 480 HEV RNA-positive blood donations during the 22-month period, most (319/480; 66%) donors were seronegative. Viral loads ranged from 1 to 3,230,000 IU/ml. All sequences belonged to genotype 3, except one which likely represents a new genotype. Most viraemic donors were over 45 years of age (279/480; 58%), donors aged between 17 and 24 years had a seven-times higher incidence of HEV infection than other donors between March and June 2016 (1:544 donations vs 1:3,830). HEV-infected blood donors were evenly distributed throughout England. Screening prevented 480 HEV RNA-positive blood donations from reaching clinical supply. Conclusion HEV screening of blood donations is a vital step in order to provide safer blood for all recipients, but especially for the immunosuppressed. The unusually high rates of HEV infection in young blood donors may provide some insight into specific risks associated with HEV infection in England.
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Affiliation(s)
- Heli Harvala
- University College London, London, United Kingdom.,Microbiology Services, NHS Blood and Transplant, London, United Kingdom
| | - Patricia E Hewitt
- Microbiology Services, NHS Blood and Transplant, London, United Kingdom
| | - Claire Reynolds
- Joint NHSBT/PHE Epidemiology Unit, Microbiology Services, NHS Blood and Transplant and Blood Safety, Hepatitis, Sexually Transmitted Infection and HIV Division, National Infections Service, Public Health England, London, United Kingdom
| | - Callum Pearson
- Joint NHSBT/PHE Epidemiology Unit, Microbiology Services, NHS Blood and Transplant and Blood Safety, Hepatitis, Sexually Transmitted Infection and HIV Division, National Infections Service, Public Health England, London, United Kingdom
| | - Becky Haywood
- Blood Borne Virus Unit, Virus Reference Department, Microbiology Services and National Infection Services, Public Health England, London, United Kingdom
| | - Kate I Tettmar
- Microbiology Services, NHS Blood and Transplant, London, United Kingdom
| | - Ines Ushiro-Lumb
- Blood Borne Virus Unit, Virus Reference Department, Microbiology Services and National Infection Services, Public Health England, London, United Kingdom.,Microbiology Services, NHS Blood and Transplant, London, United Kingdom
| | - Susan R Brailsford
- Joint NHSBT/PHE Epidemiology Unit, Microbiology Services, NHS Blood and Transplant and Blood Safety, Hepatitis, Sexually Transmitted Infection and HIV Division, National Infections Service, Public Health England, London, United Kingdom.,Microbiology Services, NHS Blood and Transplant, London, United Kingdom
| | - Richard Tedder
- Current affiliation: Imperial College London, London, United Kingdom.,Blood Borne Virus Unit, Virus Reference Department, Microbiology Services and National Infection Services, Public Health England, London, United Kingdom.,University College London, London, United Kingdom.,Microbiology Services, NHS Blood and Transplant, London, United Kingdom
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, Microbiology Services and National Infection Services, Public Health England, London, United Kingdom
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34
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Kumar M, Hooda P, Khanna M, Patel U, Sehgal D. Development of BacMam Induced Hepatitis E Virus Replication Model in Hepatoma Cells to Study the Polyprotein Processing. Front Microbiol 2020; 11:1347. [PMID: 32625196 PMCID: PMC7315041 DOI: 10.3389/fmicb.2020.01347] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/26/2020] [Indexed: 01/10/2023] Open
Abstract
The processing of polyprotein(s) to form structural and non-structural components remains an enigma due to the non-existence of an efficient and robust Hepatitis E Virus (HEV) culture system. We used the BacMam approach to construct an HEV replication model in which the HEV genome was cloned in the BacMam vector under the CMV promoter. The recombinant BacMam was used to infect Huh7 cells to transfer the HEV genome. HEV replication was authenticated by the presence of RNAs of both the polarity (+) and (-) and formation of hybrid RNA, a replication intermediate. The presence of genes for Papain-like Cysteine Protease (PCP), methyltransferase (MeT), RNA dependent RNA polymerase (RdRp), and ORF2 was confirmed by PCR amplification. Further, the infectious nature of the culture system was established as evidenced by the cross-infection of uninfected cells using the cell lysate from the infected cells. The HEV replication model was validated by detection of the ORF1 (Open Reading Frame1) encoded proteins, identified by Western blotting and Immunofluorescence by using epitope-specific antibodies against each protein. Consequently, discrete bands of 18, 35, 37, and 56 kDa corresponding to PCP, MeT, RdRp, and ORF2, respectively, were seen. Besides demonstrating the presence of non-structural enzymes of HEV along with ORF2, activity of a key enzyme, HEV-methyltransferase has also been observed. A 20% decrease in the replicative forms of RNA could be seen in presence of 100 μM Ribavirin after 48 h of treatment. The inhibition gradually increased from 0 to 24 to 48 h post-treatment. Summarily, infectious HEV culture system has been established, which could demonstrate the presence of HEV replicative RNA forms, the structural and non-structural proteins and the methyltransferase in its active form. The system may also be used to study the mechanism of action of Ribavirin in inhibiting HEV replication and develop a therapy.
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Affiliation(s)
- Manjeet Kumar
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
| | - Preeti Hooda
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
| | - Madhu Khanna
- Virology Lab, Department of Virology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
| | - Utkarsh Patel
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
| | - Deepak Sehgal
- Virology Laboratory, Department of Life Sciences, Shiv Nadar University, Greater Noida, India
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Marion O, Lhomme S, Nayrac M, Dubois M, Pucelle M, Requena M, Migueres M, Abravanel F, Peron JM, Carrere N, Suc B, Delobel P, Kamar N, Izopet J. Hepatitis E virus replication in human intestinal cells. Gut 2020; 69:901-910. [PMID: 31727684 DOI: 10.1136/gutjnl-2019-319004] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Hepatitis E virus (HEV), one of the most common agent of acute hepatitis worldwide, is mainly transmitted enterically, via contaminated water for HEV genotypes 1 (HEV1) and HEV2, or by eating raw or undercooked infected meat for HEV genotype 3 (HEV3) and HEV4. However, little is known about how the ingested HEV reaches the liver or its ability to replicate in intestinal cells. DESIGN We developed human primary cultures of small intestine epithelial cells and intestinal explants obtained from small bowel resections. The epithelial cells were also polarised on transwells. Cells were infected with Kernow-p6 strain or clinically derived virions. RESULTS Primary intestinal cells supported the growth of Kernow-p6 strain and HEV1 and HEV3 clinically derived virions. Polarised enterocytes infected with HEV1 and HEV3 strains released HEV particles vectorially: mostly into the apical compartment with a little basally. Iodixanol density gradient centrifugation of enterocyte-derived HEV virions gave bands at a density of 1.06-1.08 g/cm3, corresponding to that of quasi-enveloped HEV particles. Ribavirin therapy inhibited HEV excretion from the basal surface but not from the apical side of infected human enterocytes. HEV virions also infected intestinal tissue explants. Lastly, HEV RNA and antigen were detected in the intestinal crypts of a chronically infected patient. CONCLUSION HEV can replicate in intestinal cells and reaches the liver as quasi-enveloped virions.
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Affiliation(s)
- Olivier Marion
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, Toulouse, France.,INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Paul Sabatier University, Toulouse, France
| | - Sebastien Lhomme
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Paul Sabatier University, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
| | - Manon Nayrac
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France
| | - Martine Dubois
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
| | - Mélanie Pucelle
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
| | - Mary Requena
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
| | - Marion Migueres
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
| | - Florence Abravanel
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Paul Sabatier University, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
| | - Jean Marie Peron
- Paul Sabatier University, Toulouse, France.,Hepatology and Gastroenterology Department, Toulouse Rangueil University Hospital, Toulouse, France
| | - Nicolas Carrere
- Paul Sabatier University, Toulouse, France.,Digestive Surgery Department, Toulouse Rangueil University Hospital, Toulouse, France
| | - Bertrand Suc
- Paul Sabatier University, Toulouse, France.,Digestive Surgery Department, Toulouse Rangueil University Hospital, Toulouse, France
| | - Pierre Delobel
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Paul Sabatier University, Toulouse, France.,Department of Infectious and Tropical Diseases, Toulouse Purpan University Hospital, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, Toulouse, France.,INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France.,Paul Sabatier University, Toulouse, France
| | - Jacques Izopet
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, Toulouse, France .,Paul Sabatier University, Toulouse, France.,Virology Laboratory, National Reference Center for hepatitis E virus, Toulouse Purpan University Hospital, Toulouse, France
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Nitta S, Takahashi K, Kawai-Kitahata F, Tsuchiya J, Sato A, Miyoshi M, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Watanabe M, Asahina Y. Time course alterations of virus sequences and immunoglobulin titers in a chronic hepatitis E patient. Hepatol Res 2020; 50:524-531. [PMID: 31883166 DOI: 10.1111/hepr.13480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 12/04/2019] [Accepted: 12/23/2019] [Indexed: 02/08/2023]
Abstract
AIM Hepatitis E virus (HEV) can cause chronic infection in immunocompromised hosts. However, the dynamics of HEV during persistent infection is not well understood. To elucidate time course alterations in virus sequences and anti-HEV antibodies during persistent infection, we analyzed the HEV sequences and titers of anti-HEV antibodies from a chronic hepatitis E patient. METHODS Serum samples were obtained from a chronic hepatitis E patient under corticosteroid therapy for neurological disease. The titers of anti-HEV antibodies (immunoglobulin A, immunoglobulin M, and immunoglobulin G) in serum samples were detected by enzyme immunoassay. The full or near-full nucleotide sequences of HEV isolated from consecutive serum samples were identified and compared. Phylogenetic analysis was also performed. RESULTS Alterations of anti-HEV antibodies from a chronic hepatitis E patient were different from those previously reported in acute hepatitis E patients. The virus sequence was unchanged in the period without treatment, but nucleotide mutations were observed after ribavirin treatment was started. In addition, the sequence of this strain had extremely high identity to that isolated from swine liver in Japan. CONCLUSIONS Virus mutations in HEV emerged after ribavirin treatment was started. Sequence analysis may useful for deciding the treatment strategy for chronic hepatitis E patients who did not eliminate the virus with 3 months of RBV treatment and inferring the origin of the infection. This report provides insights into the chronicity of hepatitis E, and the impact of persistent infection and ribavirin treatment on the emergence of virus mutations.
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Affiliation(s)
- Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuaki Takahashi
- Department of Medical Sciences, Tokyo-Shinagawa Hospital, Tokyo, Japan.,Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Fukiko Kawai-Kitahata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Itsui
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Seishin Azuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,TMDU Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
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Four-year long (2014-2017) clinical and laboratory surveillance of hepatitis E virus infections using combined antibody, molecular, antigen and avidity detection methods: Increasing incidence and chronic HEV case in Hungary. J Clin Virol 2020; 124:104284. [DOI: 10.1016/j.jcv.2020.104284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/15/2020] [Accepted: 01/27/2020] [Indexed: 12/12/2022]
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Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. J Clin Med 2020; 9:E331. [PMID: 31991629 PMCID: PMC7073673 DOI: 10.3390/jcm9020331] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails.
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Affiliation(s)
- Sébastien Lhomme
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Olivier Marion
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
| | - Florence Abravanel
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Jacques Izopet
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Nassim Kamar
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
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Rossotti R, Puoti M. Sexually Transmitted Hepatitis. Sex Transm Infect 2020. [DOI: 10.1007/978-3-030-02200-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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40
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Yoshida T, Takamura M, Goto R, Takeuchi S, Tsuchiya A, Kamimura K, Tasaki M, Nakagawa Y, Saito K, Tomita Y, Terai S. Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation. Hepatol Res 2019; 49:1244-1248. [PMID: 31077507 DOI: 10.1111/hepr.13363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/28/2019] [Accepted: 05/04/2019] [Indexed: 12/16/2022]
Abstract
Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.
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Affiliation(s)
- Tomoaki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Ryo Goto
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
| | - Masayuki Tasaki
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Nakagawa
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuhide Saito
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yoshihiko Tomita
- Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan
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Todesco E, Mazzola A, Akhavan S, Abravanel F, Poynard T, Roque-Afonso AM, Peytavin G, Marcelin AG, Calmus Y, Lecuyer L, Guillemain R, Conti F. Chronic hepatitis E in a heart transplant patient: sofosbuvir and ribavirin regimen not fully effective. Antivir Ther 2019; 23:463-465. [PMID: 29504509 DOI: 10.3851/imp3227] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2018] [Indexed: 10/17/2022]
Abstract
Hepatitis E virus (HEV) can induce chronic infections in the case of immunosuppression, which are sometimes not cured with ribavirin. Furthermore, sofosbuvir is a highly potent inhibitor of HCV polymerase and was shown to inhibit HEV genotype-3 replication in vitro. We report here the outcome of sofosbuvir/ribavirin therapy on a chronic HEV infection in a heart transplant recipient non-responder to ribavirin. After 24 weeks, the regimen failed to cure the persistent HEV infection, highlighting the need of therapeutic options for HEV-infected immunosuppressed patients.
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Affiliation(s)
- Eve Todesco
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.,Department of Virology, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alessandra Mazzola
- APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie, UPMC Paris VI, Boulevard de l'Hôpital, Paris, France
| | - Sepideh Akhavan
- Department of Virology, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.,Sorbonne Universités, UPMC Univ Paris 06, CIMI-Paris UMRS CR7, Inserm U1135, PVI Team, Paris, France
| | - Florence Abravanel
- CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France.,INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
| | - Thierry Poynard
- Groupe Hospitalier Pitié Salpêtrière APHP, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938 and Institute of Cardiometabolism and Nutrition (ICAN), INSERM, Paris, France
| | | | - Gilles Peytavin
- Pharmaco-Toxicology Department, Bichat-Claude Bernard Hospital, APHP, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, IAME, INSERM UMR 1137, Paris, France
| | - Anne-Geneviève Marcelin
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.,Department of Virology, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Yvon Calmus
- APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie, UPMC Paris VI, Boulevard de l'Hôpital, Paris, France
| | - Lucien Lecuyer
- Université René Descartes, Service de Chirurgie Cardio-Vasculaire, Assistance Publique-hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
| | - Romain Guillemain
- Unité Fonctionnelle de Transplantation Thoracique, Pole Cardiovasculaire - Néphrologie - Hypertension - Diabète, Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
| | - Filomena Conti
- APHP, Hôpital Pitié-Salpêtrière, Unité Médicale de Transplantation Hépatique, Hépato-Gastro-Enterologie, UPMC Paris VI, Boulevard de l'Hôpital, Paris, France
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Abstract
Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide. It is transmitted enterically but replicates in the liver. Recent studies indicate that HEV exists in two forms: naked, nonenveloped virions that are shed into feces to mediate inter-host transmission, and membrane-cloaked, quasienveloped virions that circulate in the bloodstream to mediate virus spread within a host. Both virion types are infectious, but differ in the way they infect cells. Elucidating the entry mechanism for both virion types is essential to understand HEV biology and pathogenesis, and is relevant to the development of treatments and preventions for HEV. This review summarizes the current understanding of the cell entry mechanism for these two HEV virion types.
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Affiliation(s)
- Xin Yin
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
| | - Zongdi Feng
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
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von Felden J, Alric L, Pischke S, Aitken C, Schlabe S, Spengler U, Giordani MT, Schnitzler P, Bettinger D, Thimme R, Xhaard A, Binder M, Ayuk F, Lohse AW, Cornelissen JJ, de Man RA, Mallet V. The burden of hepatitis E among patients with haematological malignancies: A retrospective European cohort study. J Hepatol 2019; 71:465-472. [PMID: 31108159 DOI: 10.1016/j.jhep.2019.04.022] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/05/2019] [Accepted: 04/30/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The burden of hepatitis E virus (HEV) infection among patients with haematological malignancy has only been scarcely reported. Therefore, we aimed to describe this burden in patients with haematological malignancies, including those receiving allogeneic haematopoietic stem cell transplantation. METHODS We conducted a retrospective, multicentre cohort study across 11 European centres and collected clinical characteristics of 50 patients with haematological malignancy and RNA-positive, clinically overt hepatitis E between April 2014 and March 2017. The primary endpoint was HEV-associated mortality; the secondary endpoint was HEV-associated liver-related morbidity. RESULTS The most frequent underlying haematological malignancies were aggressive non-Hodgkin lymphoma (NHL) (34%), indolent NHL (iNHL) (24%), and acute leukaemia (36%). Twenty-one (42%) patients had received allogeneic haematopoietic stem cell transplantation (alloHSCT). Death with ongoing hepatitis E occurred in 8 (16%) patients, including 1 patient with iNHL and 1 patient >100 days after alloHSCT in complete remission, and was associated with male sex (p = 0.040), cirrhosis (p = 0.006) and alloHSCT (p = 0.056). Blood-borne transmission of hepatitis E was demonstrated in 5 (10%) patients, and associated with liver-related mortality in 2 patients. Hepatitis E progressed to chronic hepatitis in 17 (34%) patients overall, and in 10 (47.6%) and 6 (50%) alloHSCT and iNHL patients, respectively. Hepatitis E was associated with acute or acute-on-chronic liver failure in 4 (8%) patients with 75% mortality. Ribavirin was administered to 24 (48%) patients, with an HEV clearance rate of 79.2%. Ribavirin treatment was associated with lower mortality (p = 0.037) and by trend with lower rates of chronicity (p = 0.407) when initiated <24 and <12 weeks after diagnosis of hepatitis E, respectively. Immunosuppressive treatment reductions were associated with mortality in 2 patients (28.6%). CONCLUSION Hepatitis E is associated with mortality and liver-related morbidity in patients with haematological malignancy. Blood-borne transmission contributes to the burden. Ribavirin should be initiated early, whereas reduction of immunosuppressive treatment requires caution. LAY SUMMARY Little is known about the burden of hepatitis E among patients with haematological malignancy. We conducted a retrospective European cohort study among 50 patients with haematological malignancy, including haematopoietic stem cell transplant recipients, with clinically significant HEV infection and found that hepatitis E is associated with hepatic and extrahepatic mortality, including among patients with indolent disease or among stem cell transplant recipients in complete remission. Hepatitis E virus infection evolved to chronic hepatitis in 5 (45.5%) patients exposed to a rituximab-containing regimen and 10 (47.6%) stem cell transplant recipients. Reducing immunosuppressive therapy because of hepatitis E was associated with mortality, while early ribavirin treatment was safe and effective.
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Affiliation(s)
- Johann von Felden
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Divisions of Liver Diseases and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, Toulouse, France; UMR 152, IRD Toulouse 3 University, France
| | - Sven Pischke
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), Hamburg site, Hamburg, Germany
| | - Celia Aitken
- Virology, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom
| | - Stefan Schlabe
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Maria Teresa Giordani
- Infectious Diseases and Tropical Medicine Unit, San Bortolo Hospital, Vicenza, Italy
| | - Paul Schnitzler
- Department of Infectious Diseases, Virology, University of Heidelberg, Germany
| | - Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, Germany; Berta-Ottenstein-Program, Faculty of Medicine, University of Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, Germany
| | - Alienor Xhaard
- Service d'hématologie-greffe, Hôpital Saint-Louis, Université Paris Diderot, Paris, France
| | - Mascha Binder
- Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Francis Ayuk
- Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan J Cornelissen
- Department of Haematology, Erasmus Medical Centre, Rotterdam, Netherlands
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, Netherlands
| | - Vincent Mallet
- Hepatology Service, Assistance Publique - Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes, Paris, France; Institut National de la Santé et de la Recherche Médicale unité 1223, Institut Pasteur, Paris, France.
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Horvatits T, Schulze Zur Wiesch J, Lütgehetmann M, Lohse AW, Pischke S. The Clinical Perspective on Hepatitis E. Viruses 2019; 11:E617. [PMID: 31284447 PMCID: PMC6669652 DOI: 10.3390/v11070617] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/26/2019] [Accepted: 07/03/2019] [Indexed: 12/17/2022] Open
Abstract
Every year, there are an estimated 20 million hepatitis E virus (HEV) infections worldwide, leading to an estimated 3.3 million symptomatic cases of hepatitis E. HEV is largely circulating in the west and is associated with several hepatic and extrahepatic diseases. HEV Genotype 1 and 2 infections are waterborne and causative for epidemics in the tropics, while genotype 3 and 4 infections are zoonotic diseases and are mainly transmitted by ingestion of undercooked pork in industrialized nations. The clinical course of these infections differs: genotype 1 and 2 infection can cause acute illness and can lead to acute liver failure (ALF) or acute on chronic liver failure (ACLF) with a high mortality rate of 20% in pregnant women. In contrast, the majority of HEV GT-3 and -4 infections have a clinically asymptomatic course and only rarely lead to acute on chronic liver failure in elderly or patients with underlying liver disease. Immunosuppressed individuals infected with genotype 3 or 4 may develop chronic hepatitis E, which then can lead to life-threatening cirrhosis. Furthermore, several extra-hepatic manifestations affecting various organs have been associated with ongoing or previous HEV infections but the causal link for many of them still needs to be proven. There is no approved specific therapy for the treatment of acute or chronic HEV GT-3 or -4 infections but off-label use of ribavirin has been demonstrated to be safe and effective in the majority of patients. However, in approximately 15% of chronically HEV infected patients, cure is not possible.
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Affiliation(s)
- Thomas Horvatits
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
- Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany.
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Kamar N, Pischke S. Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031872. [PMID: 29735575 DOI: 10.1101/cshperspect.a031872] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) genotype (gt)3 and 4 infections are prevalent in industrialized and high-income countries. Although most HEV gt3 and gt4 infections are clinically silent, acute infection may be symptomatic in some patients. In persons with underlying liver disease and in elderly men, HEV infections may present as acute or acute-on-chronic liver failure. Chronic hepatitis may develop in immunosuppressed individuals, including transplant recipients, human immunodeficiency virus (HIV)-infected patients, and persons with hematologic malignancy undergoing chemotherapy, and may progress to life-threatening liver cirrhosis. Extrahepatic manifestations of infection may include neurological and renal disease. Although there is no approved specific therapy for the treatment of acute or chronic HEV gt3 or gt4 infection, off-label use of ribavirin appears to be capable of eliminating chronic HEV infection, and may reduce disease severity in patients suffering from acute liver failure.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology and Organ Transplantation, Université Paul Sabatier, Toulouse 31059, France
| | - Sven Pischke
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
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First Crystal Structure of a Nonstructural Hepatitis E Viral Protein Identifies a Putative Novel Zinc-Binding Protein. J Virol 2019; 93:JVI.00170-19. [PMID: 31019049 DOI: 10.1128/jvi.00170-19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/17/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatitis E virus (HEV) is a 7.2-kb positive-sense, single-stranded RNA virus containing three partially overlapping reading frames, ORF1 to ORF3. All nonstructural proteins required for viral replication are encoded by ORF1 and are transcribed as a single transcript. Computational analysis of the complete ORF1 polyprotein identified a previously uncharacterized region of predicted secondary structure bordered by two disordered regions coinciding partially with a region predicted as a putative cysteine protease. Following successful cloning, expression, and purification of this region, the crystal structure of the identified protein was determined and identified to have considerable structural homology to a fatty acid binding domain. Further analysis of the structure revealed a metal binding site, shown unambiguously to specifically bind zinc via a nonclassical, potentially catalytic zinc-binding motif. Based on the structural homology of the HEV protein with known structures, along with the presence of a catalytic zinc-binding motif, it is possible that the identified protein corresponds to the HEV protease, which could require activation or repression through the binding of a fatty acid. This represents a significant step forward in the characterization and the understanding of the molecular mechanisms of the HEV genome. We present analysis for the first time of this identified nonstructural protein, expanding the knowledge and understanding of the complex mechanisms of HEV biology.IMPORTANCE Hepatitis E virus (HEV) is an emerging virus found predominately in developing countries; it causes an estimated 20 million infections, which result in approximately 57,000 deaths a year. Although it is known that the nonstructural proteins of HEV ORF1 are expressed as a single transcript, there is debate as to whether ORF1 functions as a single polyprotein or if it is processed into separate domains via a viral or endogenous cellular protease. Here we present the first structural and biophysical characterization of an HEV nonstructural protein using a construct that has partially overlapping boundaries with the predicted putative cysteine protease.
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Netzler NE, Enosi Tuipulotu D, Vasudevan SG, Mackenzie JM, White PA. Antiviral Candidates for Treating Hepatitis E Virus Infection. Antimicrob Agents Chemother 2019; 63:e00003-19. [PMID: 30885901 PMCID: PMC6535575 DOI: 10.1128/aac.00003-19] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 03/04/2019] [Indexed: 12/14/2022] Open
Abstract
Globally, hepatitis E virus (HEV) causes significant morbidity and mortality each year. Despite this burden, there are no specific antivirals available to treat HEV patients, and the only licensed vaccine is not available outside China. Ribavirin and alpha interferon are used to treat chronic HEV infections; however, severe side effects and treatment failure are commonly reported. Therefore, this study aimed to identify potential antivirals for further development to combat HEV infection. We selected 16 compounds from the nucleoside and nonnucleoside antiviral classes that range in developmental status from late preclinical to FDA approved and evaluated them as potential antivirals for HEV infection, using genotype 1 replicon luminescence studies and replicon RNA quantification. Two potent inhibitors of HEV replication included NITD008 (half-maximal effective concentration [EC50], 0.03 μM; half-maximal cytotoxic concentration [CC50], >100 μM) and GPC-N114 (EC50, 1.07 μM, CC50, >100 μM), and both drugs reduced replicon RNA levels in cell culture (>50% reduction with either 10 μM GPC-N114 or 2.50 μM NITD008). Furthermore, GPC-N114 and NITD008 were synergistic in combinational treatment (combination index, 0.4) against HEV replication, allowing for dose reduction indices of 20.42 and 8.82 at 50% inhibition, respectively. Sofosbuvir has previously exhibited mixed results against HEV as an antiviral, both in vitro and in a few clinical applications; however, in this study it was effective against the HEV genotype 1 replicon (EC50, 1.97 μM; CC50, >100 μM) and reduced replicon RNA levels (47.2% reduction at 10 μM). Together these studies indicate drug repurposing may be a promising pathway for development of antivirals against HEV infection.
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Affiliation(s)
- Natalie E Netzler
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia
| | - Daniel Enosi Tuipulotu
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia
| | | | - Jason M Mackenzie
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Peter A White
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia
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Abstract
Liver transplantation has become an important treatment modality for patients with end-stage liver disease/cirrhosis, acute liver failure, and hepatocellular carcinoma. Although surgical techniques and immunosuppressive regimens for liver transplantation have improved significantly over the past 20 years, infectious complications continue to contribute to the morbidity and mortality in this patient population. The use of standardized screening protocols for both donors and recipients, coupled with targeted prophylaxis against specific pathogens, has helped to mitigate the risk of infection in liver transplant recipients. Patients with chronic liver disease and cirrhosis have immunological deficits that place them at increased risk for infection while awaiting liver transplantation. The patient undergoing liver transplantation is prone to develop healthcare-acquired infections due to multidrug-resistant organisms that could potentially affect patient outcomes after transplantation. The complex nature of liver transplant surgery that involves multiple vascular and hepatobiliary anastomoses further increases the risk of infection after liver transplantation. During the early post-transplantation period, healthcare-acquired bacterial and fungal infections are the most common types of infection encountered in liver transplant recipients. The period of maximal immunosuppression that occurs at 1–6 months after transplantation can be complicated by opportunistic infections due to both primary infection and reactivation of latent infection. Severe community-acquired infections can complicate the course of liver transplantation beyond 12 months after transplant surgery. This chapter provides an overview of liver transplantation including indications, donor-recipient selection criteria, surgical procedures, and immunosuppressive therapies. A focus on infections in patients with chronic liver disease/cirrhosis and an overview of the specific infectious complications in liver transplant recipients are presented.
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Dalton HR, Izopet J. Transmission and Epidemiology of Hepatitis E Virus Genotype 3 and 4 Infections. Cold Spring Harb Perspect Med 2018. [PMID: 29530946 DOI: 10.1101/cshperspect.a032144] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Following the introduction of robust serological and molecular tools, our understanding of the epidemiology of zoonotic hepatitis E virus (HEV) has improved considerably in recent years. Current thinking suggests that consumption of pork meat products is the key route of infection in humans, but it is certainly not the only one. Other routes of infection include environmental spread, contaminated water, and via the human blood supply. The epidemiology of HEV genotype (gt)3 and gt4 is complex, as there are several sources and routes of infection, and it is likely that these vary between and within countries and over time.
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Affiliation(s)
- Harry R Dalton
- Royal Cornwall Hospital, Truro TR1 3LJ, United Kingdom.,European Centre for Environment and Human Health, University of Exeter, Truro TR1 3LJ, United Kingdom
| | - Jacques Izopet
- Department of Virology, Hepatitis E Virus National Reference Centre, Toulouse University Hospital, 31059 Toulouse, France.,Toulouse-Purpan Centre for Pathophysiology, INSERM UMR1043/CNRS UMR 5282, CPTP, Toulouse University Paul Sabatier, 31024 Toulouse, France
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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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