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While RNA modifications like N\u2076-methyladenosine (m\u2076A) regulate viral replication, their role in maintaining HIV-1 latency is poorly defined. Here, we identify the RNA-binding protein RBM39 as a scaffold organizing an m\u2076A-dependent silencing complex that enforces viral latency. Through proteomic and functional analyses, we demonstrate that RBM39 recruits the m\u2076A reader YTHDC1 and the RNA helicase DDX5, forming a tripartite complex that accelerates Tat RNA decay and enforces viral quiescence. Genetic or pharmacological degradation of RBM39 (using the clinically explored molecular glue\n                    <jats:italic>indisulam<\/jats:italic>\n                    ) potently reactivates latent HIV-1 in J-Lat cell models, primary CD4\u207a T cells from people living with HIV-1 (PLWH), and synergizes with established LRAs (Bryostatin-1, JQ-1, SAHA) to broadly activate proviral reservoirs. Our work reveals a previously unrecognized host pathway in which RBM39-organized RNA decay complexes silence HIV-1 through epitranscriptomic regulation of Tat. In addition to establishing RBM39 as a promising therapeutic target for addressing the limitations of current \u201cshock and kill\u201d strategies, our findings establish a novel mechanistic framework for m\u2076A-dependent regulation of viral gene expression. This framework may serve as a valuable reference for investigating similar regulatory mechanisms in other latent viral infections or oncogenic processes where RNA methylation plays a pivotal role.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003486","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T18:36:56Z","timestamp":1762886216000},"page":"e3003486","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["The RNA-binding protein RBM39 scaffolds an m\u2076A-dependent RNA decay complex that destabilizes Tat transcripts and restricts HIV-1 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