Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo - PubMed (original) (raw)

Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo

José M Cuevas et al. J Virol. 2009 Jun.

Abstract

Their extremely error-prone replication makes RNA viruses targets for lethal mutagenesis. In the case of hepatitis C virus (HCV), the standard treatment includes ribavirin, a base analog with an in vitro mutagenic effect, but the in vivo mode of action of ribavirin remains poorly understood. Here, we test the mutagenic effects of ribavirin plus interferon treatment in vivo using a new method to estimate mutation rates based on the analysis of nonsense mutations. We apply this methodology to a large HCV sequence database containing over 15,000 reverse transcription-PCR molecular clone sequences from 74 patients infected with HCV. We obtained an estimate of the spontaneous mutation rate of ca. 10(-4) substitutions per site or lower, a value within the typically accepted range for RNA viruses. A roughly threefold increase in mutation rate and a significant shift in mutation spectrum were observed in samples from patients undergoing 6 months of interferon plus ribavirin treatment. This result is consistent with the known in vitro mutagenic effect of ribavirin and suggests that the antiviral effect of ribavirin plus interferon treatment is at least partly exerted through lethal mutagenesis.

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References

1. 1. Aaskov, J., K. Buzacott, H. M. Thu, K. Lowry, and E. C. Holmes. 2006. Long-term transmission of defective RNA viruses in humans and Aedes mosquitoes. Science 311236-238. - PubMed
2. 1. Anderson, J. P., R. Daifuku, and L. A. Loeb. 2004. Viral error catastrophe by mutagenic nucleosides. Annu. Rev. Microbiol. 58183-205. - PubMed
3. 1. Asahina, Y., N. Izumi, N. Enomoto, M. Uchihara, M. Kurosaki, Y. Onuki, Y. Nishimura, K. Ueda, K. Tsuchiya, H. Nakanishi, T. Kitamura, and S. Miyake. 2005. Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C. J. Hepatol. 43623-629. - PubMed
4. 1. Belshaw, R., A. Gardner, A. Rambaut, and O. G. Pybus. 2008. Pacing a small cage: mutation and RNA viruses. Trends Ecol. Evol. 23188-193. - PMC - PubMed
5. 1. Bracho, M. A., F. Y. Carrillo-Cruz, E. Ortega, A. Moya, and F. González-Candelas. 2006. A new subtype of hepatitis C virus genotype 1: complete genome and phylogenetic relationships of an Equatorial Guinea isolate. J. Gen. Virol. 871697-1702. - PubMed

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