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Hepatitis C Virus Genotype 1-6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness and Resistance Patterns in the Context of the Infectious Viral Life Cycle

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Hepatitis C virus (HCV) NS3 protease inhibitors (PIs) are important components of novel HCV therapy regimens. Studies of PI resistance initially focused on genotype 1. Therefore, knowledge on determinants of PI resistance for the highly prevalent genotypes 2-6 remains limited. Using Huh7.5 cell-culture infectious HCV recombinants with genotype 1-6 NS3 protease, we identified protease positions 54, 155 and 156 as hotspots for selection of resistance substitutions under treatment with the first licensed PIs telaprevir and boceprevir. Treatment of genotype 2 with newer PIs vaniprevir, faldaprevir, simeprevir, grazoprevir, paritaprevir and deldeprevir identified positions 156 and 168 as hotspots for resistance; substitution Y56H emerged for 3 newer PIs. Substitution selection also depended on the specific recombinant. Identified substitutions conferred cross-resistance to several PIs, however, most substitutions selected under telaprevir/boceprevir conferred less resistance to certain newer PIs. In a single-cycle production assay, across genotypes, PI treatment primarily decreased viral replication, which was rescued by PI resistance substitutions. Identified substitutions resulted in differential effects on viral fitness, depending on the original recombinant and the substitution. Across genotypes, fitness impairment induced by resistance substitutions was primarily due to decreased replication. Most identified combinations of substitutions increased resistance or fitness. Combinations of resistance substitutions with fitness compensating substitutions either rescued replication or compensated for decreased replication with increased assembly. This comprehensive study provides insight into selection patterns and effects of PI resistance substitutions for HCV genotypes 1-6 in the context of the infectious viral life cycle, which is of interest for clinical and virological HCV research.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Issue number6
Pages (from-to)3563-3578
Publication statusPublished - Jun 2016

ID: 46365432