Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment

• Published in: Scientific reports Vol. 7; no. 1; p. 41719
• Main Authors: Eltahla, Auda A., Leung, Preston, Pirozyan, Mehdi R., Rodrigo, Chaturaka, Grebely, Jason, Applegate, Tanya, Maher, Lisa, Luciani, Fabio, Lloyd, Andrew R., Bull, Rowena A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.01.2017; Nature Publishing Group
• Subjects: 13; 13/21; 45; 45/23; 45/77; 631/250/2161; 631/326/596/1905; 82; 96; Amino Acid Substitution; Antiviral agents; Antiviral Agents - pharmacology; CD8 antigen; Disease resistance; Drug Resistance, Viral; Epitopes; Evolution, Molecular; Genome, Viral; Genomes; Genotype; Hepacivirus - drug effects; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - virology; Histocompatibility antigen HLA; Humanities and Social Sciences; Humans; Longitudinal Studies; Lymphocytes T; multidisciplinary; Mutation; Reproductive fitness; Science; Science (multidisciplinary); T-Lymphocytes - metabolism; Viral Nonstructural Proteins - genetics; Whole Genome Sequencing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep41719

Resistance against new hepatitis C virus (HCV) antivirals is an area of increasing interest. Resistance-associated substitutions (RASs) have been identified in treatment-naïve individuals, but pressures driving treatment-independent RAS emergence are poorly understood. We analysed the longitudinal evolution of RASs in twelve participants with early acute HCV infections. Full-genome deep sequences were analysed for changes in RAS frequency within NS3, NS5A and NS5B-coding regions over the course of the infection. Emergence of RASs relevant only to the polymerase non-nucleoside inhibitors (NNI) was detected, and these lay within CD8+ T-cell epitopes. Conversely, the loss of NNI RASs over time appeared likely to be driven by viral fitness constraints. These results highlight the importance of monitoring CD8+ T cell epitope-associated RASs in populations with dominant HLA types.