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

Autoři: Tian-hao Zhang aff001;  Lei Dai aff002;  John P. Barton aff003;  Yushen Du aff004;  Yuxiang Tan aff002;  Wenwen Pang aff006;  Arup K. Chakraborty aff007;  James O. Lloyd-Smith aff009;  Ren Sun aff005
Působiště autorů: Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA aff001;  CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China aff002;  Department of Physics and Astronomy, University of California, Riverside, CA 92521, USA aff003;  School of Medicine, ZheJiang University, Hangzhou, 210000, China aff004;  Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA aff005;  Department of Public Health Laboratory Science, West China School of Public Health, Sichuan University, Chengdu 610041, China aff006;  Institute for Medical Engineering and Science, Departments of Chemical Engineering, Physics, & Chemistry, Massachusetts Institute of Technology, MA 21309, USA aff007;  Ragon Institute of MGH, MIT, & Harvard, Cambridge, MA 21309, USA aff008;  Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA aff009
Vyšlo v časopise: Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease. PLoS Genet 16(10): e32767. doi:10.1371/journal.pgen.1009009
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009009


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.

Klíčová slova:

Deletion mutation – HIV – HIV-1 – Protease inhibitors – Proteases – Viral evolution – Viral replication – Fitness epistasis


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