title: Identification of HCV protease inhibitor resistance mutations by selection pressure-based method.
abstract: A major challenge to successful antiviral therapy is the emergence of drug-resistant viruses. Recent studies have developed several automated analyses of HIV sequence polymorphism based on calculations of selection pressure (K(a)/K(s)) to predict drug resistance mutations. Similar resistance analysis programs for HCV inhibitors are not currently available. Taking advantage of the recently available sequence data of patient HCV samples from a Phase II clinical study of protease inhibitor boceprevir, we calculated the selection pressure for all codons in the HCV protease region (amino acid 1-181) to identify potential resistance mutations. The correlation between mutations was also calculated to evaluate linkage between any two mutations. Using this approach, we identified previously known major resistant mutations, including a recently reported mutation V55A. In addition, a novel mutation V158I was identified, and we further confirmed its resistance to boceprevir in protease enzyme and replicon assay. We also extended the approach to analyze potential interactions between individual mutations and identified three pairs of correlated changes. Our data suggests that selection pressure-based analysis and correlation mapping could provide useful tools to analyze large amount of sequencing data from clinical samples and to identify new drug resistance mutations as well as their linkage and correlations.
authors.affiliation: Molecular Design and Informatics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. ping.qiu@spcorp.com
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.forename: Vincent
authors.initials: V
authors.lastname: Sanfiorenzo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Curry
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Shaotang
authors.initials: S
authors.lastname: Liu
authors.forename: Angela
authors.initials: A
authors.lastname: Skelton
authors.forename: Ellen
authors.initials: E
authors.lastname: Xia
authors.forename: Constance
authors.initials: C
authors.lastname: Cullen
authors.forename: Robert
authors.initials: R
authors.lastname: Ralston
authors.forename: Jonathan
authors.initials: J
authors.lastname: Greene
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D004252:DNA Mutational Analysis / Q000379:methods*; D024882:Drug Resistance, Viral / Q000235:genetics*; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011392:Proline; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide