{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T11:13:26Z","timestamp":1770462806985,"version":"3.49.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Fulbright-CONICET Scholar Award","award":["AI116167"],"award-info":[{"award-number":["AI116167"]}]},{"name":"Basic Science Core of the Texas D-CFAR","award":["AI161943"],"award-info":[{"award-number":["AI161943"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+\u200aG140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200\u2005bp fragment spanning amino acids 85\u2013150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105\u2013106\u2005pg\/mL) for WT and NL4-3-Q148H; by contrast, it was low (102\u2013104\u2005pg\/mL) for both F1(BF)-Q148H\u200a+\u200aG140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P\u200a=\u200a0.05), 9-fold for URTR23-Q148H (P\u200a=\u200a0.01) and 16000-fold for ARMA159-Q148H (P\u200a=\u200a0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jac\/dkac238","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T03:49:21Z","timestamp":1658980161000},"page":"2793-2802","source":"Crossref","is-referenced-by-count":1,"title":["HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H"],"prefix":"10.1093","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6760-842X","authenticated-orcid":false,"given":"Paula C","family":"Aulicino","sequence":"first","affiliation":[{"name":"Laboratory of Cellular Biology and Retroviruses, Unit of Virology and Molecular Epidemiology, Hospital de Pediatr\u00eda \u201cProf. Dr. Juan P. 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Garrahan\u201d , Buenos Aires , Argentina"},{"name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET) , Buenos Aires , Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Monzon","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology & Microbiology, Baylor College of Medicine , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Solange","family":"Arazi-Caillaud","sequence":"additional","affiliation":[{"name":"Unit of Epidemiology and Infectology, Hospital de Pediatr\u00eda \u201cProf. Dr. Juan P. Garrahan\u201d , Buenos Aires , Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Bologna","sequence":"additional","affiliation":[{"name":"Unit of Epidemiology and Infectology, Hospital de Pediatr\u00eda \u201cProf. Dr. Juan P. Garrahan\u201d , Buenos Aires , Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Mangano","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Biology and Retroviruses, Unit of Virology and Molecular Epidemiology, Hospital de Pediatr\u00eda \u201cProf. Dr. Juan P. 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