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Among the clinically relevant latency reversing agents (LRA) under investigation, the <jats:italic>\u03b3<\/jats:italic>c-cytokine IL-15 and the superagonist N-803 have been shown to reactivate latent HIV <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. However, their clinical benefit can be hindered by IL-15 promoting survival of infected cells. We previously identified a small molecule, HODHBt, that sensitizes latently infected cells to death upon reactivation with <jats:italic>\u03b3<\/jats:italic>c-cytokines through a STAT-dependent pathway. In here, we aimed to identify and evaluate FDA-approved compounds that could also sensitize HIV-infected cells to apoptosis. Using the Connectivity Map (CMap), we identified the retinol derivative 13-<jats:italic>cis<\/jats:italic>-retinoic acid (Isotretinoin) causes similar transcriptional changes as HODHBt. Isotretinoin enhances IL-15-mediated latency reversal without inducing proliferation of memory CD4 T cells. <jats:italic>Ex vivo<\/jats:italic> analysis of PBMCs from ACTG A5325, where Isotretinoin was administered to ART-suppressed people with HIV, showed that Isotretinoin treatment enhances IL-15-mediated latency reversal. Furthermore, we showed that a combination of IL-15 with Isotretinoin promotes the reduction of translation-competent reservoirs <jats:italic>ex vivo<\/jats:italic>. Mechanistically, combination of IL-15 and Isotretinoin increases caspase-3 activation specifically in HIV-infected cells but not uninfected cells. Our results suggest that Isotretinoin can be a novel approach to target and eliminate translation-competent HIV reservoirs.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012601","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T17:35:59Z","timestamp":1728927359000},"page":"e1012601","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells"],"prefix":"10.1371","volume":"20","author":[{"given":"J. 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