{"doi":"10.1126/sciadv.adg5953","title":"Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants","abstract":"HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. 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-Å 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.","journal":"Science Advances","year":2023,"id":323074,"datarank":0.8433398641949335,"base_score":3.6635616461296463,"endowment":3.6635616461296463,"self_citation_contribution":0.5495342469194471,"citation_network_contribution":0.2938056172754863,"self_endowment_contribution":0.5495342469194471,"citer_contribution":0.2938056172754863,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":22,"citers_with_citation_signal":14,"citers_with_endowment":14,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":true,"deposit_databanks":{"Protein":["PDB 8FN7","PDB 8FND","PDB 8FNH","PDB 8FNJ","PDB 8FNL","PDB 8FNM","PDB 8FNP","PDB 8FNQ"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275236,"name":"Dario Oliveira Passos","orcid":"0000-0003-1333-9102","position":1,"is_corresponding":false},{"id":895210,"name":"Zelin Shan","orcid":"0000-0003-4983-3575","position":2,"is_corresponding":false},{"id":275242,"name":"Steven J. Smith","orcid":"0000-0001-9207-1671","position":3,"is_corresponding":false},{"id":523725,"name":"Qinfang Sun","orcid":"0000-0001-7362-1543","position":4,"is_corresponding":false},{"id":820664,"name":"Avik Biswas","orcid":"0000-0002-3519-3944","position":5,"is_corresponding":false},{"id":922808,"name":"Indrani Choudhuri","orcid":"0000-0002-5829-4625","position":6,"is_corresponding":false},{"id":329382,"name":"Timothy S. Strutzenberg","orcid":"0000-0003-0598-534X","position":7,"is_corresponding":false},{"id":333535,"name":"Allan Haldane","orcid":"0000-0002-8343-1994","position":8,"is_corresponding":false},{"id":494456,"name":"Nanjie Deng","orcid":"0000-0001-8805-3526","position":9,"is_corresponding":false},{"id":991231,"name":"Zhaoyang Li","orcid":"0000-0003-1743-6444","position":10,"is_corresponding":false},{"id":275239,"name":"Xue Zhi Zhao","orcid":"0000-0003-1006-6364","position":11,"is_corresponding":false},{"id":860534,"name":"Lorenzo Briganti","orcid":"0000-0003-2237-6896","position":12,"is_corresponding":false},{"id":324221,"name":"Mamuka Kvaratskhelia","orcid":"0000-0003-3800-0033","position":13,"is_corresponding":false},{"id":275243,"name":"Terrence R. Burke","orcid":"0000-0001-9925-8586","position":14,"is_corresponding":false},{"id":333536,"name":"Ronald M. Levy","orcid":"0000-0001-8696-5177","position":15,"is_corresponding":false},{"id":258968,"name":"Stephen H. Hughes","orcid":"0000-0002-9176-4377","position":16,"is_corresponding":false},{"id":275244,"name":"Robert Craigie","orcid":"0000-0001-9516-6385","position":17,"is_corresponding":false},{"id":275245,"name":"Dmitry Lyumkis","orcid":"0000-0002-8124-7472","position":18,"is_corresponding":false},{"id":1037304,"name":"Min Li","orcid":"0000-0002-7119-2148","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T01:07:47.432636Z","pmid":"37478179","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}