title: Mutagenic Effects of Ribavirin on Hepatitis E Virus-Viral Extinction versus Selection of Fitness-Enhancing Mutations.
abstract: Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.
authors.affiliation: Institute of Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany. Daniel.Todt@twincore.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Todt
authors.affiliation: Institute of Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany. Stephaniewalter@gmx.de.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Walter
authors.affiliation: Institute of Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany. Richard.Brown@twincore.de.
authors.forename: Richard J P
authors.initials: RJ
authors.lastname: Brown
authors.affiliation: Institute of Experimental Virology, Twincore-Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany. Eike.Steinmann@twincore.de.
authors.forename: Eike
authors.initials: E
authors.lastname: Steinmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003332:Coronaviridae; D024882:Drug Resistance, Viral; D016751:Hepatitis E / Q000188:drug therapy / Q000821:virology; D016752:Hepatitis E virus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009153:Mutagens / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation; D012254:Ribavirin / Q000494:pharmacology* / Q000627:therapeutic use; D012641:Selection, Genetic; D016896:Treatment Outcome; D014774:Virulence; D014780:Viruses
chemical_list: D000998:Antiviral Agents; D009153:Mutagens; D012254:Ribavirin
keywords: RNA viruses; hepatitis E virus; intra-host population; mutagenesis; ribavirin