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Here, we report that ectopic expression of AST in CD4\n            <jats:sup>+<\/jats:sup>\n            T cells from people living with HIV-1 undergoing antiretroviral therapy hinders the reactivation of viral transcription in response to ex vivo stimulation with pharmacologic and T cell receptor agonists, thus preventing the reversal of latency. We defined the structural domains and sequence motifs of AST that contribute to its latency-promoting functions. Last, we carried out an unbiased proteomic screen of AST interactors that revealed an array of host factors both previously known and not known to suppress HIV-1 expression. Our studies identify AST as a first-in-class biological molecule that is capable of enforcing HIV-1 latency and with actionable curative potential.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adu8014","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T17:58:21Z","timestamp":1746813501000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["Suppression of HIV-1 transcription and latency reversal via ectopic expression of the viral antisense transcript AST"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9473-1366","authenticated-orcid":true,"given":"Rui","family":"Li","sequence":"first","affiliation":[{"name":"Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7863-0489","authenticated-orcid":true,"given":"Kaveh","family":"Daneshvar","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1572-1382","authenticated-orcid":true,"given":"Xinjie","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-711X","authenticated-orcid":true,"given":"Michelle","family":"Pleet","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6384-1550","authenticated-orcid":true,"given":"Grace","family":"Igbinosun","sequence":"additional","affiliation":[{"name":"Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0353-3561","authenticated-orcid":true,"given":"Mohd Shameel","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatah","family":"Kashanchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4096-3106","authenticated-orcid":true,"given":"Alan C.","family":"Mullen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2070-297X","authenticated-orcid":true,"given":"Fabio","family":"Romerio","sequence":"additional","affiliation":[{"name":"Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA."},{"name":"W. 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