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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,9]]},"abstract":"<jats:p>Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.<\/jats:p>","DOI":"10.1073\/pnas.2316662121","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T15:04:10Z","timestamp":1711983850000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3519-3944","authenticated-orcid":false,"given":"Avik","family":"Biswas","sequence":"first","affiliation":[{"name":"Center for Biophysics and Computational Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122"},{"name":"Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037"},{"name":"Department of Physics, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indrani","family":"Choudhuri","sequence":"additional","affiliation":[{"name":"Center for Biophysics and Computational Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122"},{"name":"Department of Chemistry, Temple University, Philadelphia, PA 19122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-9622","authenticated-orcid":false,"given":"Eddy","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8124-7472","authenticated-orcid":false,"given":"Dmitry","family":"Lyumkis","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037"},{"name":"Graduate School of Biological Sciences, Department of Molecular Biology, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Haldane","sequence":"additional","affiliation":[{"name":"Center for Biophysics and Computational Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122"},{"name":"Department of Physics, Temple University, Philadelphia, PA 19122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald M.","family":"Levy","sequence":"additional","affiliation":[{"name":"Center for Biophysics and Computational Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122"},{"name":"Department of Chemistry, Temple University, Philadelphia, PA 19122"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,4]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"UNAIDS The path that ends AIDS: UNAIDS Global AIDS Update 2023 (Joint United Nations Programme on HIV\/AIDS Geneva 2023). https:\/\/www.UNAIDSunaids.org\/en\/resources\/fact-sheet (UNAIDS 2022). 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