{"doi":"10.1093/jac/dkad390","title":"Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy","abstract":"BACKGROUND: Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. METHODS: HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. RESULTS: In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. CONCLUSIONS: Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.","journal":"Journal of Antimicrobial Chemotherapy","year":2023,"id":354584,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9466,"is_data_producer":false,"deposit_databanks":null,"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":994743,"name":"Suman Sharma","orcid":null,"position":1,"is_corresponding":false},{"id":757696,"name":"Khanghy Truong","orcid":null,"position":2,"is_corresponding":false},{"id":1102635,"name":"Vindhya Kukunoor","orcid":null,"position":3,"is_corresponding":false},{"id":1102636,"name":"Karm Ghei","orcid":null,"position":4,"is_corresponding":false},{"id":981879,"name":"Solange Arazi-Caillaud","orcid":null,"position":5,"is_corresponding":false},{"id":1102637,"name":"Moira Taicz","orcid":null,"position":6,"is_corresponding":false},{"id":814998,"name":"Rosa Bologna","orcid":"0000-0002-2853-0981","position":7,"is_corresponding":false},{"id":981516,"name":"Andrea Mangano","orcid":"0000-0002-6273-7628","position":8,"is_corresponding":false},{"id":279021,"name":"Jason T. Kimata","orcid":"0000-0002-0504-0090","position":9,"is_corresponding":false},{"id":787089,"name":"Paula Aulicino","orcid":"0000-0002-6760-842X","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T01:13:11.976628Z","pmid":"38153245","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":[]}