Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

• DOI: 10.1371/journal.pgen.1009009
• Publication Date: 2020-10-21T17:37:13Z
• Authors: Tian-hao Zhang; Lei Dai; John P. Barton; Yushen Du; Yuxiang Tan; Wenwen Pang; Arup K. Chakraborty; James O. Lloyd-Smith; Ren Sun
• Keywords: Epistasis; Fitness landscape; Reversion; Genetic Fitness; Resistance mutation; Viral evolution

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 in evolution drug resistance has been overlooked clinical studies or vitro selection experiments, as these observations capture outcome selection. In this study, we systematically profile landscape resistance-associated sites HIV-1 protease using deep mutational scanning. We construct mutant library covering combinations at 11 protease, all which are associated with to inhibitors clinic. Using sequencing, quantify thousands mutants after multiple cycles human T cells. Although majority effects viral replication, find epistasis among is predominantly positive. Furthermore, our data consistent genetic interactions inferred directly from HIV sequence patients. Fitness valleys formed strong positive reduce likelihood reversal Overall, results support view involved emergence clinically observed and provide insights understanding barriers reversion resistance.