Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications.
Positive strand RNA virus populations are a collection of similar but genetically different viruses. They exist as viral quasispecies due to the high mutation rates of the low fidelity viral RNA-dependent RNA polymerase (RdRp). It is thought that this genomic heterogeneity is advantageous to the population, allowing for adaptation to rapidly changing environments that present varying types and degrees of selective pressure. However, one consequence of this extensive diversity is the susceptibility to mutagens that further increase sequence variation. Since RNA viruses live at the edge of maximal variability, an increase in the mutation rate is likely to force the virus beyond the tolerable mutation frequency into 'error catastrophe'. One such mutagen, ribavirin, is an antiviral nucleoside analog that is mutagenic to several RNA viruses. Ribavirin is incorporated into the viral genome causing lethal mutagenesis and a subsequent decrease in the specific infectivity. Even so, passaging poliovirus in the presence of low to intermediate concentrations of the drug leads to the emergence of a viral population resistant to the effects of ribavirin. These viruses have a point mutation in the RdRp that increases the overall polymerase fidelity. Interestingly, as predicted by the quasispecies theory, ribavirin resistant viruses are less adaptable, as they are more susceptible to other non-mutagenic antiviral drugs and are highly attenuated in vivo. Here, we review the mechanism of action of ribavirin on poliovirus and other RNA viruses, the possibility for escape via increased fidelity of the viral polymerase, the consequences of this response on viral population dynamics, and the biological implications for the therapeutic use of mutagenic antiviral agents.
Vignuzzi
Marco
M
Department of Microbiology and Immunology, University of California, Mission Bay, Genentech Hall, Box 2280, San Francisco CA 94143-2280, USA.
Stone
Jeffrey K
JK
Andino
Raul
R
D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D009154:Mutation; D017955:Poliovirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology*
D000998:Antiviral Agents; D012254:Ribavirin; D012324:RNA-Dependent RNA Polymerase