Next generation sequencing of the hepatitis C virus NS5B gene reveals potential novel S282 drug resistance mutations
| Autor: | Robert A. Kozak, Gary Van Domselaar, David La, John Kim, Dominic Vallee, Lynne Leonard, Paul Sandstrom, Mia J. Biondi, James Brooks, Richard Pilon, Hezhao Ji, Ben Binhua Liang |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Sofosbuvir Hepatitis C virus In silico Mutation Missense Hepacivirus Drug resistance Viral Nonstructural Proteins Biology medicine.disease_cause NS5B Drug resistance mutation Antiviral Agents Cohort Studies chemistry.chemical_compound Virology Drug Resistance Viral medicine Humans Substance Abuse Intravenous Genetics Mutation Ribavirin Pyrosequencing High-Throughput Nucleotide Sequencing virus diseases Nucleoside inhibitor Hepatitis C Chronic Middle Aged digestive system diseases Treatment Outcome chemistry HCV In silico molecular modeling Female Mutant Proteins medicine.drug |
| Zdroj: | Virology. 477:1-9 |
| ISSN: | 0042-6822 |
| DOI: | 10.1016/j.virol.2014.12.037 |
| Popis: | Identifying HCV drug resistance mutations (DRMs) is increasingly important as new direct acting antiviral therapies (DAA) become available. Tagged pooled pyrosequencing (TPP) was originally developed as cost-effective approach for detecting low abundance HIV DRMs. Using 127 HCV-positive samples from a Canadian injection drug user cohort, we demonstrated the suitability and efficiency of TPP for evaluating DRMs in HCV NS5B gene. At a mutation identification threshold of 1%, no nucleoside inhibitor DRMs were detected among these DAA naïve subjects. Clinical NS5B resistance to non-nucleoside inhibitors and interferon/ribavirin was predicted to be low within this cohort. S282T mutation, the primary mutation selected by sofosbuvir in vitro, was not identified while S282G/C/R variants were detected in 9 subjects. Further characterization on these new S282 variants using in silico molecular modeling implied their potential association with resistance. Combining TPP with in silico analysis detects NS5B polymorphisms that may explain differences in treatment outcomes. |
| Databáze: | OpenAIRE |
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