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Journal of Virology, June 2009, p. 5760-5764, Vol. 83, No. 11
0022-538X/09/$08.00+0     doi:10.1128/JVI.00201-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo{triangledown} ,§

José M. Cuevas,1,2,3 Fernando González-Candelas,1,2,3,4 Andrés Moya,1,2,3,4 and Rafael Sanjuán1,2*

Institut Cavanilles de Biodiversitat y Biología Evolutiva,1 Departamento de Genética, Universitat de Valencia, Valencia, Spain,2 CIBER en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain,3 Área Genómica y Salud, CSISP, Valencia, Spain4

Received 28 January 2009/ Accepted 17 March 2009

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.

* Corresponding author. Mailing address: Institut Cavanilles de Biodiversitat i Biologia Evolutiva, Universitat de València, P.O. Box 22085, 46071 València, Spain. Phone: 34 963 543 629. Fax: 34 963 543 670. E-mail: rafael.sanjuan{at}uv.es

{triangledown} Published ahead of print on 25 March 2009.

§ Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, June 2009, p. 5760-5764, Vol. 83, No. 11
0022-538X/09/$08.00+0     doi:10.1128/JVI.00201-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dapp, M. J., Clouser, C. L., Patterson, S., Mansky, L. M. (2009). 5-Azacytidine Can Induce Lethal Mutagenesis in Human Immunodeficiency Virus Type 1. J. Virol. 83: 11950-11958 [Abstract] [Full Text]  


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