title: Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment.
abstract: 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.
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Auda A
authors.initials: AA
authors.lastname: Eltahla
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Preston
authors.initials: P
authors.lastname: Leung
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Mehdi R
authors.initials: MR
authors.lastname: Pirozyan
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Chaturaka
authors.initials: C
authors.lastname: Rodrigo
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Grebely
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Tanya
authors.initials: T
authors.lastname: Applegate
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Maher
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Fabio
authors.initials: F
authors.lastname: Luciani
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lloyd
authors.affiliation: School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Rowena A
authors.initials: RA
authors.lastname: Bull
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008137:Longitudinal Studies; D009154:Mutation; D013601:T-Lymphocytes / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics; D000073336:Whole Genome Sequencing
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins