{"doi":"10.1093/jac/dkab448","title":"Specific mutations in the HIV-1 G-tract of the 3′-polypurine tract cause resistance to integrase strand transfer inhibitors","abstract":"BACKGROUND: In vitro selection experiments identified viruses resistant to integrase strand transfer inhibitors (INSTIs) carrying mutations in the G-tract (six guanosines) of the 3'-polypurine tract (3'-PPT). A clinical study also reported that mutations in the 3'-PPT were observed in a patient receiving dolutegravir monotherapy. However, recombinant viruses with the 3'-PPT mutations that were found in the clinical study were recently shown to be susceptible to INSTIs. OBJECTIVES: To identify the specific mutation(s) in the G-tract of the 3'-PPT for acquiring INSTI resistance, we constructed infectious clones bearing single or multiple mutations and systematically characterized the susceptibility of these clones to both first- and second-generation INSTIs. METHODS: The infectious clones were tested for their infectivity and susceptibility to INSTIs in a single-cycle assay using TZM-bl cells. RESULTS: A single mutation of thymidine (T) at the fifth position (GGG GTG) in the G-tract of the 3'-PPT had no effect on INSTI resistance. A double mutation, cytidine (C) or 'T' at the second position and 'T' at the fifth position (GCG GTG and GTG GTG), increased resistance to INSTIs, with the appearance of a plateau in the maximal percentage inhibition (MPI) of the dose-response curves, consistent with a non-competitive mechanism of inhibition. CONCLUSIONS: Mutations at the second and fifth positions in the G-tract of the 3'-PPT may result in complex resistance mechanism(s), rather than simply affecting INSTI binding at the IN active site.","journal":"Journal of Antimicrobial Chemotherapy","year":2021,"id":183156,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":736800,"name":"Mai Kubota","orcid":null,"position":1,"is_corresponding":false},{"id":736801,"name":"Urara Shigemi","orcid":null,"position":2,"is_corresponding":false},{"id":736316,"name":"Hirotaka Ode","orcid":"0000-0001-8624-2382","position":3,"is_corresponding":false},{"id":736317,"name":"Yoshiyuki Yokomaku","orcid":"0000-0002-6342-544X","position":4,"is_corresponding":false},{"id":494263,"name":"Karen A. Kirby","orcid":"0000-0003-2468-4796","position":5,"is_corresponding":false},{"id":253448,"name":"Stefan G. Sarafianos","orcid":"0000-0002-5840-154X","position":6,"is_corresponding":false},{"id":736318,"name":"Yasumasa Iwatani","orcid":"0000-0001-9269-4828","position":7,"is_corresponding":false},{"id":494961,"name":"Atsuko Hachiya","orcid":null,"position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:48:17.816498Z","pmid":"34894227","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":[]}