In vitro selection of resistance to sofosbuvir in HCV replicons of genotype 1 to 6.

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Citation

Xu S, Doehle B, Rajyaguru S, Han B, Barauskas O, Feng J, Perry J, Dvory-Sobol H, Svarovskaia ES, Miller MD, Mo H

In vitro selection of resistance to sofosbuvir in HCV replicons of genotype 1 to 6.

Antivir Ther. 2017 Mar 1. doi: 10.3851/IMP3149.

PubMed ID
28248189 [ View in PubMed
]
Abstract

BACKGROUND: Sofosbuvir is a nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase approved for treatment of HCV-infected patients in combination with ribavirin or with other antivirals. It has activity against all genotypes of HCV. Resistance to sofosbuvir in genotype 1 and 2 HCV is conferred by the S282T substitution in NS5B. METHODS: To begin to define the correlates of resistance to sofosbuvir in other genotypes, we performed selection experiments in cell culture using cell lines containing subgenomic replicons derived from genotypes 1b, 2a, 3a, and 4a, or chimeric replicons in a genotype 1b background but encoding genotype 2b, 5a, and 6a NS5B polymerase. RESULTS: In every case, S282T was selected following passage in the presence of increasing concentrations of sofosbuvir for 10 to 15 weeks. When introduced as a site-directed mutant, S282T conferred reductions in sofosbuvir susceptibility of between 2.4 and 19.4-fold. Other substitutions observed during the selections had relatively less impact on susceptibility, such as N237S in genotype 6a (2.5-fold). Replication capacity was affected by the introduction of S282T in all genotypes to variable extents (3.2% to 22% of wild-type). CONCLUSIONS: These results confirm that S282T is the primary sofosbuvir resistance-associated substitution and that replication capacity is reduced when it is present in all genotypes of HCV.

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