title: A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients.
abstract: We analyzed blood samples collected from 15 patients with chronic hepatitis E who were recipients of solid-organ transplants. All patients cleared the hepatitis E virus (HEV) except for 2 (nonresponders); 1 patient died. A G1634R mutation in viral polymerase was detected in the HEV RNA of the nonresponders; this mutation did not provide the virus with resistance to ribavirin in vitro. However, the mutant form of a subgenomic replicon of genotype 3 HEV replicated more efficiently in vitro than HEV without this mutation, and the same was true for infectious virus, including in competition assays. Similar results were obtained for genotype 1 HEV. The G1634R mutation therefore appears to increase the replicative capacity of HEV in the human liver and hence reduce the efficacy of ribavirin.
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Debing
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Center of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Gisa
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Kai
authors.initials: K
authors.lastname: Dallmeier
authors.affiliation: MVZ für Lebertransplantation, University Hospital Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Pischke
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Center of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Bremer
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Center of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Center of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Center of Internal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Pothakamuri Venkata
authors.initials: PV
authors.lastname: Suneetha
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium. Electronic address: johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005838:Genotype; D056945:Hep G2 Cells; D016751:Hepatitis E / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D016752:Hepatitis E virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D006521:Hepatitis, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016377:Organ Transplantation / Q000009:adverse effects*; D010641:Phenotype; D012254:Ribavirin / Q000627:therapeutic use*; D013997:Time Factors; D014162:Transfection; D017211:Treatment Failure; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D012321:DNA-Directed RNA Polymerases
keywords: Drug Resistant; Mechanism; RNA-Dependent RNA Polymerase; Virulence