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Biswas A , Haldane A , Arnold E , Levy RM
Epistasis and entrenchment of drug resistance in HIV-1 subtype B
Elife. 2019 Oct 8;8
PMID: 31591964    PMCID: PMC6783267    URL: https://www.ncbi.nlm.nih.gov/pubmed/31591964
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The development of drug resistance in HIV is the result of primary mutations whose effects on viral fitness depend on the entire genetic background, a phenomenon called 'epistasis'. Based on protein sequences derived from drug-experienced patients in the Stanford HIV database, we use a co-evolutionary (Potts) Hamiltonian model to provide direct confirmation of epistasis involving many simultaneous mutations. Building on earlier work, we show that primary mutations leading to drug resistance can become highly favored (or entrenched) by the complex mutation patterns arising in response to drug therapy despite being disfavored in the wild-type background, and provide the first confirmation of entrenchment for all three drug-target proteins: protease, reverse transcriptase, and integrase; a comparative analysis reveals that NNRTI-induced mutations behave differently from the others. We further show that the likelihood of resistance mutations can vary widely in patient populations, and from the population average compared to specific molecular clones.
2050-084x Biswas, Avik Orcid: 0000-0002-3519-3944 Haldane, Allan Orcid: 0000-0002-8343-1994 Arnold, Eddy Levy, Ronald M Orcid: 0000-0001-8696-5177 U54-GM103368/NH/NIH HHS/United States R01-GM030580/NH/NIH HHS/United States S10OD020095/NH/NIH HHS/United States 1R35GM132090/NH/NIH HHS/United States Journal Article Research Support, N.I.H., Extramural England Elife. 2019 Oct 8;8. pii: 50524. doi: 10.7554/eLife.50524.