Ribavirin's antiviral mechanism of action: lethal mutagenesis?

Ribavirin, an antiviral drug discovered in 1972, is interesting and important for three reasons: (a) it exhibits antiviral activity against a broad range of RNA viruses; (b) it is currently used clinically to treat hepatitis C virus infections, respiratory syncytial virus infections, and Lassa fever virus infections; and (c) ribavirin's mechanism of action has remained unclear for many years. Here we recount the history of ribavirin and review recent reports regarding ribavirin's mechanism of action, including our studies demonstrating that ribavirin is an RNA virus mutagen and ribavirin's primary antiviral mechanism of action against a model RNA virus is via lethal mutagenesis of the RNA virus genomes. Implications for the development of improved versions of ribavirin and for the development of novel antiviral drugs are discussed.