Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications
Section snippets
Poliovirus exists on the edge of error catastrophe: the safety of living dangerously
Poliovirus, the prototype picornavirus, is a non-enveloped virus with a single stranded RNA genome of positive polarity. The virion is composed of an icosahedral protein shell composed of four capsid proteins VP1, VP2, VP3 and VP4 encompassing the RNA genome. The genome of approximately 7.5 kb contains a single ORF encoding a polyprotein that is cleaved into the individual viral proteins required for virus replication and assembly. Poliovirus has a characteristically rapid multiplication cycle
Ribavirin induces lethal mutagenesis of poliovirus
Ribavirin has a broad-spectrum antiviral activity against both RNA and DNA viruses. A number of viruses in different taxonomic viral families are susceptible to ribavirin (summarized in Table 1). Yet, the mechanisms by which ribavirin inhibits these different viruses has been difficult to elucidate, as this drug has pleiotropic effects. The inhibition of cellular inosine monophosphate dehydrogenase (IMPDH) and subsequent decrease of intracellular GTP levels can reduce viral protein translation
A high fidelity polymerase confers resistance to lethal mutagenesis
Indeed, passage of poliovirus in ribavirin treated cells resulted in the acquisition of a RdRp mutant with a glycine to serine mutation at position 64 (G64S) of the polymerase (Pfeiffer and Kirkegaard, 2003, Vignuzzi et al., 2004). Interestingly, examination of the known crystal-derived structure (Hansen et al., 1997) of the poliovirus RdRp revealed that this mutation was not found within any of the known functional domains but was situated within the small region spanning the finger and thumb
Ribavirin and RNA mutagens as antivirals: biological implications for diverse virus families
As highlighted above, ribavirin is a potent antiviral that exerts its effects through lethal mutagenesis. The poliovirus model is an excellent system for these studies, as the effects of RNA mutagens can be readily measured and compared in tissue culture or in animal models. Furthermore, established biochemical approaches permit analysis of parameters useful in determining ideal RNA mutagens. Ribavirin analogs can be developed and quickly tested in such a system, in order to identify which
Acknowledgements
This work was financially supported by an NIH fellowship to J.S. and by NIH grant AI40085 to R.A. We would like to thank R. Van Rij, C. Ruiz-Jarabo, and O. Peersen for helpful discussions.
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Both authors contributed equally to this review.