{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T08:26:36Z","timestamp":1773217596097,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tenofovir alafenamide (TAF) is a prodrug of the nucleoside reverse transcriptase (RT) inhibitor tenofovir (TFV). Compared to the earlier TFV prodrug, TFV disoproxil fumarate (TDF), TAF achieves more than fourfold\u2010higher intracellular levels of its active metabolite TFV diphosphate (TFV\u2010DP) in clinical studies, while achieving a significant reduction of TFV systemic exposure. Resistance to TFV has been well established, with the K65R mutation in\u00a0RT\u00a0as the signature mutation.\u00a0Here we evaluated the in vitro activity of TAF and TDF in patient\u2010derived HIV\u20101 isolates harboring the K65R mutation.\u00a0Clinical isolates containing K65R were cloned into the pXXLAI construct (<jats:italic>n<\/jats:italic>\u2009=\u200942). In vitro phenotypic susceptibility of the constructs to TAF and TDF was evaluated in an MT\u20102 cell HIV assay and in viral breakthrough assays modeling physiological concentrations of TAF and TDF.\u00a0TAF and TDF susceptibility were highly correlated in K65R\u2010containing mutants, ranging from 2.7\u2010 to 3.0\u2010fold (K65R alone) and 1.2\u2010 to 27.6\u2010fold (K65R+\u2009other RT mutations) relative to wild\u2010type. In viral breakthrough assays mimicking differences in physiological concentrations, TAF inhibited breakthrough of 40 of 42 clinical isolates, while the TDF equivalent only inhibited 32 of 42 isolates tested.\u00a0TAF displayed a higher barrier to resistance than TDF in this panel of K65R\u2010containing clinical isolates.<\/jats:p>","DOI":"10.1002\/jmv.28723","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T05:36:32Z","timestamp":1681882592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antiviral activity of tenofovir alafenamide (TAF) against HIV\u20101 clinical isolates harboring K65R"],"prefix":"10.1002","volume":"95","author":[{"given":"Stephanie","family":"Cox","sequence":"first","affiliation":[{"name":"HIV Clinical Virology Gilead Sciences, Inc. Foster City California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0911-4237","authenticated-orcid":false,"given":"Nicolas","family":"Margot","sequence":"additional","affiliation":[{"name":"HIV Clinical Virology Gilead Sciences, Inc. Foster City California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Callebaut","sequence":"additional","affiliation":[{"name":"HIV Clinical Virology Gilead Sciences, Inc. Foster City California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"U.S. Department of Health & Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV.\u00a0January 20 2022. 2022."},{"key":"e_1_2_9_3_1","first-page":"1","volume-title":"Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a Public Health Approach","author":"World Health Organization (WHO).\u00a0","year":"2021"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.5.1898-1906.2005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60616-X"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2015.11.009"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2018.03.012"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200206140-00004"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1086\/381784"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.10.4971-4977.2006"},{"issue":"8","key":"e_1_2_9_11_1","first-page":"2249","article-title":"Differential detection of M184V\/I between plasma historical HIV genotypes and HIV proviral DNA from PBMCs","volume":"75","author":"Margot N","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00816-06"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01151-15"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.03.007"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1086\/314560"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308806200"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2016.05.012"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2011.12.008"},{"issue":"3","key":"e_1_2_9_19_1","first-page":"111","article-title":"2019 update of the drug resistance mutations in HIV\u20101","volume":"27","author":"Wensing AM","year":"2019","journal-title":"Top Antivir Med"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.4.920-928.2000"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e31817bbe93"}],"container-title":["Journal of Medical Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.28723","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T08:02:30Z","timestamp":1692259350000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmv.28723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4]]},"references-count":20,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1002\/jmv.28723"],"URL":"https:\/\/doi.org\/10.1002\/jmv.28723","archive":["Portico"],"relation":{},"ISSN":["0146-6615","1096-9071"],"issn-type":[{"value":"0146-6615","type":"print"},{"value":"1096-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4]]},"assertion":[{"value":"2022-11-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e28723"}}