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Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency
18:10

Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency

Published on: June 16, 2011

Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis

Ana M Ortega-Prieto1, Julie Sheldon, Ana Grande-Pérez

  • 1Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.

Plos One
|August 27, 2013
PubMed

Insights

Ribavirin induces lethal mutagenesis, increasing mutations and extinguishing hepatitis C virus (HCV) in cell culture. This antiviral strategy counteracts viral adaptation by enhancing mutation rates, unlike mycophenolic acid which also inhibits HCV without mutagenesis.

Area of Science:

  • Virology
  • Antiviral Therapy
  • Molecular Biology

Background:

  • Lethal mutagenesis is an antiviral strategy to prevent viral escape mutants by increasing mutation rates.
  • Hepatitis C virus (HCV) poses a significant global health challenge, necessitating novel therapeutic approaches.
  • Ribavirin, a purine nucleoside analogue, is used in HCV therapy, but its mutagenic potential requires investigation.

Purpose of the Study:

  • To determine if ribavirin acts as a mutagenic agent during HCV replication in cell culture.
  • To investigate the mechanism of ribavirin-induced HCV extinction.
  • To compare ribavirin's mutagenic effects with mycophenolic acid.

Main Methods:

  • Serial passages of HCV in human hepatoma Huh-7.5 cells.
  • Analysis of viral progeny production and mutant spectrum complexity.
  • Measurement of intracellular nucleoside-triphosphate concentrations, including GTP.

Main Results:

  • Ribavirin increased mutant spectrum complexity and specific transition types, leading to HCV extinction.
  • Ribavirin-mediated HCV extinction involved a decrease in specific infectivity, characteristic of lethal mutagenesis.
  • Mycophenolic acid extinguished HCV without increasing mutation complexity, despite similar GTP depletion.

Conclusions:

  • Ribavirin functions as a mutagenic agent against HCV, inducing lethal mutagenesis and viral extinction.
  • The mutagenic activity of ribavirin is distinct from its effect on intracellular GTP levels.
  • Lethal mutagenesis represents a promising antiviral strategy for combating HCV.

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