A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity

Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7289-94. doi: 10.1073/pnas.1232294100. Epub 2003 May 16.

Abstract

Ribavirin is a nucleotide analog that can be incorporated by viral polymerases, causing mutations by allowing base mismatches. It is currently used therapeutically as an antiviral drug during hepatitis C virus infections. During the amplification of poliovirus genomic RNA or hepatitis C replicons, error frequency is known to increase upon ribavirin treatment. This observation has led to the hypothesis that ribavirin's antiviral activity results from error catastrophe caused by increased mutagenesis of viral genomes. Here, we describe the generation of ribavirin-resistant poliovirus by serial viral passage in the presence of increasing concentrations of the drug. Ribavirin resistance can be caused by a single amino acid change, G64S, in the viral polymerase in an unresolved portion of the fingers domain. Compared with wild-type virus, ribavirin-resistant poliovirus displays increased fidelity of RNA synthesis in the absence of ribavirin and increased survival both in the presence of ribavirin and another mutagen, 5-azacytidine. Ribavirin-resistant poliovirus represents an unusual class of viral drug resistance: resistance to a mutagen through increased fidelity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antiviral Agents / pharmacology
  • Base Sequence
  • DNA, Viral / genetics
  • Drug Resistance, Viral / genetics
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Point Mutation*
  • Poliovirus / drug effects
  • Poliovirus / enzymology*
  • Poliovirus / genetics*
  • RNA, Viral / biosynthesis
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / genetics*
  • Ribavirin / pharmacology

Substances

  • Antiviral Agents
  • DNA, Viral
  • RNA, Viral
  • Ribavirin
  • RNA-Dependent RNA Polymerase