8 research outputs found
HCV p7 as a novel vaccine-target inducing multifunctional CD4<sup>+</sup> and CD8<sup>+</sup> T-cells targeting liver cells expressing the viral antigen
Pre-existing, treatment-specific resistance-associated substitutions in hepatitis C virus genotype 1 and 3 and viral RNA titers during treatment with direct-acting antivirals
Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants
Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistanceâassociated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1â4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156âRASs were not maintained. For genotypes 1 and 2, persistence of 156âRASs depended on genomeâwide substitution networks, coâselected under continued PI treatment and identified by nextâgeneration sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156âRASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and preâexisting A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156âRASs, we observed genomeâwide selection of substitutions under treatment. Conclusion : Comprehensive PI resistance profiling for HCV genotypes 1â6 revealed 156âRASs as key determinants of highâlevel resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1â3 156âvariants, which might pose a threat to clinically relevant combination treatments