{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:28:18Z","timestamp":1787016498326,"version":"build-2736575974"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T00:00:00Z","timestamp":1720483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T00:00:00Z","timestamp":1720483200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Merck"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,7,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits HIV-1 at multiple stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for the treatment of HIV-1. Here, we characterized ISL and LEN\n                      <jats:italic>in vitro<\/jats:italic>\n                      to assess combinatorial antiviral activity, cytotoxicity, and the potential for interactions between the two compounds. Bliss analysis revealed ISL with LEN demonstrated additive inhibition of HIV-1 replication, with no evidence of antagonism across the range of concentrations tested. ISL exhibited potent antiviral activity against variants encoding known LEN resistance-associated mutations (RAMs) with or without the presence of M184V, an ISL RAM in reverse transcriptase (RT) . Static resistance selection experiments were conducted with ISL and LEN alone and in combination, initiating with either wild-type virus or virus containing the M184I RAM in RT to further assess their barrier to the emergence of resistance. The combination of ISL with LEN more effectively suppressed viral breakthrough at lower multiples of the compounds\u2019 IC\n                      <jats:sub>50<\/jats:sub>\n                      (half-maximal inhibitory concentration) values and fewer mutations emerged with the combination compared to either compound on its own. The known pathways for development of resistance with ISL and LEN were not altered, and no novel single mutations emerged that substantially reduced susceptibility to either compound. The lack of antagonism and cross-resistance between ISL and LEN support the ongoing evaluation of the combination for treatment of HIV-1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00334-24","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T09:07:02Z","timestamp":1718183222000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["No antagonism or cross-resistance and a high barrier to the emergence of resistance\n                    <i>in vitro<\/i>\n                    for the combination of islatravir and lenacapavir"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4672-8641","authenticated-orcid":false,"given":"Tracy L.","family":"Diamond","sequence":"first","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih Lin","family":"Goh","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winnie","family":"Ngo","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silveria","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xu","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Klein","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay A.","family":"Grobler","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5238-6529","authenticated-orcid":false,"given":"Ernest","family":"Asante-Appiah","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Rahway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.562694"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.036616"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2014.03.001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605223113"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2443-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00133-22"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02223-21"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02057-20"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiac364"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2008.04.007"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2697"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.07.014"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviromet.2010.02.002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90097-7"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-3542(90)90001-n"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1177\/135965350501000"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab503"},{"key":"e_1_3_3_19_2","volume-title":"IAS Conference on HIV Science (IAS 2019), July 21-24","author":"Yant SRM","year":"2019","unstructured":"Yant SRM, Mulato A, Hansen D, Thielan A, Schroeder SD, Porter D, White K, Daumer M, Tse WC, Cihlar T. 2019. \u201cIn vitro resistance profile of GS-6207, a first-in-class picomolar HIV capsid inhibitor in clinical development as a novel long-acting antiretroviral agent\u201d IAS Conference on HIV Science (IAS 2019), July 21-24; Mexico City, Mexico"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01167-21"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg100"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb4808"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01804-22"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00334-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00334-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T09:04:49Z","timestamp":1720515889000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00334-24"}},"subtitle":[],"editor":[{"given":"Miguel Angel","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,9]]},"references-count":22,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7,9]]}},"alternative-id":["10.1128\/aac.00334-24"],"URL":"https:\/\/doi.org\/10.1128\/aac.00334-24","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,9]]},"assertion":[{"value":"2024-02-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00334-24"}}