{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T08:13:27Z","timestamp":1778314407033,"version":"3.51.4"},"reference-count":28,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Staff Scientist\/Staff Clinician Research Award (SSSC-RA)","award":["Z01-BC 006150"],"award-info":[{"award-number":["Z01-BC 006150"]}]},{"name":"Staff Scientist\/Staff Clinician Research Award (SSSC-RA)","award":["Z01-BC 007363"],"award-info":[{"award-number":["Z01-BC 007363"]}]},{"name":"Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute, National Institutes of Health","award":["Z01-BC 006150"],"award-info":[{"award-number":["Z01-BC 006150"]}]},{"name":"Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute, National Institutes of Health","award":["Z01-BC 007363"],"award-info":[{"award-number":["Z01-BC 007363"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Second-generation integrase strand transfer inhibitors (INSTIs) are strongly recommended for people living with HIV-1 (PLWH). The emergence of resistance to second-generation INSTIs has been infrequent and has not yet been a major issue in high-income countries. However, the delayed rollouts of these INSTIs in low- to middle-income countries during the COVID-19 pandemic combined with increased transmission of drug-resistant mutants worldwide are leading to an increase in INSTI resistance. Herein, we evaluated the antiviral potencies of our lead developmental INSTI 4d and the second-generation INSTIs dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) against a panel of IN quadruple mutants. The mutations are centered around G140S\/Q148H, including positions L74, E92, and T97 combined with E138A\/K\/G140S\/Q148H. All of the tested INSTIs lose potency against these IN quadruple mutants compared with the wild-type IN. In single-round infection assays, compound 4d retained higher antiviral potencies (EC50 values) than second-generation INSTIs against a subset of quadruple mutants. These findings may advance understanding of mechanisms that contribute to resistance and, in so doing, facilitate development of new INSTIs with improved antiviral profiles.<\/jats:p>","DOI":"10.3390\/v17010121","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T06:46:10Z","timestamp":1737009970000},"page":"121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparative Analyses of Antiviral Potencies of Second-Generation Integrase Strand Transfer Inhibitors (INSTIs) and the Developmental Compound 4d Against a Panel of Integrase Quadruple Mutants"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-1671","authenticated-orcid":false,"given":"Steven J.","family":"Smith","sequence":"first","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-6364","authenticated-orcid":false,"given":"Xue Zhi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9176-4377","authenticated-orcid":false,"given":"Stephen H.","family":"Hughes","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9925-8586","authenticated-orcid":false,"suffix":"Jr.","given":"Terrence R.","family":"Burke","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Smith, S.J., Zhao, X.Z., Passos, D.O., Lyumkis, D., Burke, T.R., and Hughes, S.H. 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