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We found that most of the proteins that were increased\u2014about 66.7%\u2014were involved in immune response pathways. Of these, 23.3% were specifically related to type I interferon (IFN-I) signaling, which remains active in the brain through both HIV-related and unrelated mechanisms. Using single-cell RNA sequencing (scRNA-seq) on brain tissues collected during rapid autopsies from participants in the Last Gift cohort, we found that IFN-I signaling was especially strong in astrocytes, microglia (MG), and endothelial cells. In a mini-brain organoid model of acute HIV infection, IFN-I signaling was also highly active in astrocytes but less so in MG. Interestingly, IFN-I activation can happen without HIV being present\u2014expression of human endogenous retrovirus-W1 (HERV-W1) Env can directly trigger this response in astrocytes, and it continues in glial cells even with effective ART. Together, our findings point to persistent IFN-I activation in glial and endothelial cells in the brain, which may contribute to neuroinflammation and cognitive disorders in PWH on ART.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013411","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T17:39:46Z","timestamp":1755711586000},"page":"e1013411","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Persistent type I interferon signaling within the brain of people with HIV on ART with cognitive impairment"],"prefix":"10.1371","volume":"21","author":[{"given":"Yuyang","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciniso 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