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Mechanisms regulating viral persistence are not well understood; thus, there is a compelling need for research focusing on addressing the knowledge gap related to HIV persistence. The present study focuses on the effect of extracellular condensates (ECs) on latent HIV\/SIV reactivation in the brain in the context of HIV infection using the SIV-infected rhesus macaque model. We used in vitro model systems of post-integration latency and primary peripheral blood mononuclear cells isolated from HIV-infected ART-suppressed donors to explore the role of basal ganglia (BG) isolated extracellular condensates (ECs) in reprogramming HIV latent cells. We found that BG ECs from uninfected macaques (VEH) and SIV infected macaques (VEH\u2009|\u2009SIV) activated latent HIV transcription in various model systems. VEH\u2009|\u2009SIV ECs significantly increased the expression and production of viral antigen in latently infected cells. Activation of viral transcription, antigen expression, and latency reactivation was inhibited by ECs from the brain of macaques treated with Delta-9-tetrahydrocannabinol (THC) and infected with SIV (THC\u2009|\u2009SIV). Virus produced by latently infected cells treated with VEH\u2009|\u2009SIV ECs potentiated cell-cell and cell-free HIV transmission. VEH\u2009|\u2009SIV ECs also reversed dexamethasone-mediated inhibition of HIV transcription while TNF\u03b1-mediated reactivation of latency was reversed by THC\u2009|\u2009SIV ECs. Transcriptome and secretome analyses of total RNA and supernatants from latently infected cells treated with ECs revealed significant alterations in gene expression and cytokine secretion. THC\u2009|\u2009SIV ECs increased secretion of Th2 and decreased secretion of proinflammatory cytokines. Most strikingly, while VEH\/SIV ECs robustly induced expression of HIV RNA in latently HIV-infected cells, increased the frequency of HIV gag p24 expressing cells in HIV-infected CD4\u2009+\u2009T cells within PBMCs, and production of extracellular HIV gag p24, long-term low-dose THC administration enriched ECs with anti-inflammatory cargo that significantly diminished their ability to reactivate latent HIV, an indication that ECs are endogenous host factors that may regulate HIV persistence.<\/jats:p>","DOI":"10.1038\/s41380-025-03354-w","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T13:10:01Z","timestamp":1764421801000},"page":"2232-2249","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extracellular condensates (ECs) are endogenous modulators of HIV transcription and latency reactivation"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2375-082X","authenticated-orcid":false,"given":"Wasifa","family":"Naushad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakmini S.","family":"Premadasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyshnavi","family":"Tallapaneni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6844-1035","authenticated-orcid":false,"given":"Bryson C.","family":"Okeoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack T.","family":"Stapleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-3277","authenticated-orcid":false,"given":"Mahesh","family":"Mohan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-6493","authenticated-orcid":false,"given":"Chioma M.","family":"Okeoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"3354_CR1","doi-asserted-by":"publisher","first-page":"2862","DOI":"10.1172\/JCI98968","volume":"128","author":"JB Honeycutt","year":"2018","unstructured":"Honeycutt JB, Liao B, Nixon CC, Cleary RA, Thayer WO, Birath SL, et al. 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