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• W3093804778 endingPage "e1009009" @default.
• W3093804778 startingPage "e1009009" @default.
• W3093804778 abstract "Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance." @default.
• W3093804778 created "2020-10-29" @default.
• W3093804778 creator A5000987778 @default.
• W3093804778 creator A5020079595 @default.
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• W3093804778 creator A5036998304 @default.
• W3093804778 creator A5049439879 @default.
• W3093804778 creator A5052657259 @default.
• W3093804778 creator A5061654582 @default.
• W3093804778 creator A5070393163 @default.
• W3093804778 creator A5076253719 @default.
• W3093804778 date "2020-10-21" @default.
• W3093804778 modified "2023-09-26" @default.
• W3093804778 title "Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease" @default.
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