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RNA virus error catastrophe: direct molecular test by using ribavirin.

S Crotty1, C E Cameron, R Andino

  • 1Department of Microbiology and Immunology, University of California, 513 Parnassus Avenue, Box 0414, San Francisco, CA 94143, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 24, 2001
PubMed
Summary

The antiviral drug ribavirin causes lethal mutagenesis in RNA viruses, leading to error catastrophe and loss of infectivity. This study directly demonstrates ribavirin

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Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • RNA viruses exhibit rapid evolution due to high mutation frequencies.
  • Quasispecies theory suggests RNA viruses are susceptible to error catastrophe.
  • Ribavirin, an antiviral drug, was previously proposed to act as an RNA virus mutagen causing error catastrophe.

Purpose of the Study:

  • To directly demonstrate error catastrophe in RNA viruses using ribavirin.
  • To confirm ribavirin's antiviral mechanism as lethal mutagenesis.
  • To investigate the susceptibility of poliovirus to ribavirin-induced error catastrophe.

Main Methods:

  • Utilized poliovirus as a model RNA virus.
  • Administered ribavirin to induce mutagenesis.
  • Quantified viral genome infectivity and mutation frequency.

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  • Constructed a graph of error catastrophe based on mutation levels and infectivity.

    • Main Results:

    • Demonstrated ribavirin's antiviral activity through lethal mutagenesis.
    • Observed a 99.3% loss in poliovirus genome infectivity after one infection round.
    • Showed a 9.7-fold increase in mutagenesis with sufficient ribavirin concentrations.
    • Established that poliovirus exists at the edge of viability, susceptible to error catastrophe.

    Conclusions:

    • Ribavirin's antiviral effect is directly mediated by lethal mutagenesis.
    • Error catastrophe is a viable mechanism for controlling RNA virus replication.
    • RNA virus mutagens represent a promising new class of antiviral therapeutics.