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Contribution of a mutational bias in hepatitis C virus replication to the genetic barrier in the development of drug resistance.

Research paper by Megan H MH Powdrill, Egor P EP Tchesnokov, Robert A RA Kozak, Rodney S RS Russell, Ross R Martin, Evguenia S ES Svarovskaia, Hongmei H Mo, Roger D RD Kouyos, Matthias M Götte

Indexed on: 03 Dec '11Published on: 03 Dec '11Published in: PNAS



Abstract

The development of resistance to direct-acting antivirals (DAAs) targeting the hepatitis C virus (HCV) can compromise therapy. However, mechanisms that determine prevalence and frequency of resistance-conferring mutations remain elusive. Here, we studied the fidelity of the HCV RNA-dependent RNA polymerase NS5B in an attempt to link the efficiency of mismatch formation with genotypic changes observed in vivo. Enzyme kinetic measurements revealed unexpectedly high error rates (approximately 10(-3) per site) for G:U/U:G mismatches. The strong preference for G:U/U:G mismatches over all other mistakes correlates with a mutational bias in favor of transitions over transversions. Deep sequencing of HCV RNA samples isolated from 20 treatment-naïve patients revealed an approximately 75-fold difference in frequencies of the two classes of mutations. A stochastic model based on these results suggests that the bias toward transitions can also affect the selection of resistance-conferring mutations. Collectively, the data provide strong evidence to suggest that the nature of the nucleotide change can contribute to the genetic barrier in the development of resistance to DAAs.