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The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-\u00c5 resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A\/S + Q148H\/K\/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.<\/jats:p>","DOI":"10.1126\/sciadv.adg5953","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T13:58:59Z","timestamp":1689947939000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":39,"title":["Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7119-2148","authenticated-orcid":true,"given":"Min","family":"Li","sequence":"first","affiliation":[{"name":"National Institute of Diabetes and Digestive Diseases, National Institutes of Health, Bethesda, MD, 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1333-9102","authenticated-orcid":true,"given":"Dario","family":"Oliveira 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