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Abstract Details
Establishment of robust HCV genotype 4d, 5a, and 6a replicon systems
Camus G1, Xu S2, Han B2, Lu J2, Dvory-Sobol H2, Yu M2, Cheng G2, Miller MD2, Doehle BP2, Mo H2. Virology. 2017 Nov 22;514:134-141. doi: 10.1016/j.virol.2017.11.003. [Epub ahead of print]
Author information
1
Gilead Sciences, Foster City, CA, USA. Electronic address: Gregory.Camus@gilead.com.
2
Gilead Sciences, Foster City, CA, USA.
Abstract
Hepatitis C Virus (HCV) is a diverse human pathogen which displays ~15% divergence at the subtype level. To facilitate development of antivirals with pan-genotype activity, we developed the first genotype 4d subgenomic replicon, as well as new replicons for genotypes 5a, and 6a. Adaptive mutations developed in these replicons differ greatly across genotypes. Their impacts on the replication capacity were tested using site-directed mutants. In the genotype 4d replicon, single mutations have moderate effect, but the double mutation NS4A-Q34R+NS5A-S232G increased the replication capacity by 161-fold. These new stable replicon cell lines were used to determine the antiviral activity of HCV inhibitors. The NS3 protease inhibitor voxilaprevir, NS5A second generation inhibitor velpatasvir, and NS5B nucleoside analog inhibitor sofosbuvir, had similar antiviral activities across the different genotypes/subtypes tested, while the NS5A first generation inhibitor, ledipasvir, had very good antiviral activity against GT1, 4, 5, and 6 in vitro.