{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T10:12:03Z","timestamp":1772273523588,"version":"3.50.1"},"reference-count":63,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"28","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2023,7,14]]},"abstract":"<jats:p>\n            Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV\n            <jats:sub>KGD<\/jats:sub>\n            ) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV\n            <jats:sub>KGD<\/jats:sub>\n            was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC\n            <jats:sub>50<\/jats:sub>\n            of 130 femtomolar. When cells were exposed to HIV\n            <jats:sub>KGD<\/jats:sub>\n            IN\u2013containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS\u2019s putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142\u2013bound HIV\n            <jats:sub>KGD<\/jats:sub>\n            \u2019s PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant\u2013harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adg2955","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T17:58:38Z","timestamp":1689184718000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7089-831X","authenticated-orcid":true,"given":"Manabu","family":"Aoki","sequence":"first","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA."},{"name":"Department of Medical Technology, Kumamoto Health Science University, 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