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The chronic generation of HIV-1 Transactivator of transcription (Tat) likely contributes to HAND via direct neuronal toxicity and glial-mediated toxicity. This review summarizes our current understanding of how chronic Tat generation from microglia and astrocytes promote glutamate excitotoxicity.<\/jats:p>\n <\/jats:sec>\n \n Recent findings<\/jats:title>\n In recent years, the indirect effects of Tat through the activation of glial cells have gained significant interest. This review highlights microglia and astrocytes as HIV-1 reservoirs that release Tat protein in the central nervous system. Specific context is provided on the Tat isoforms and models in the recent literature and their impact on our understanding of the neuronal and glial-mediated effects of Tat on glutamate transmission.<\/jats:p>\n <\/jats:sec>\n \n Summary<\/jats:title>\n Transgenic and transduction models of HIV-1 Tat expression in glia have demonstrated Tat-induced glial activation phenotypes that contribute to dysregulation of glutamate receptors and transporters. Investigating both glial-mediated and direct mechanisms of Tat-potentiated excitotoxicity can identify therapeutic targets that are relevant for HAND.<\/jats:p>\n <\/jats:sec>","DOI":"10.1007\/s11904-026-00789-w","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:51:02Z","timestamp":1781509862000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HIV-1 Tat-driven Glutamate Dysregulation: Implications for Cognitive Impairment in HAND"],"prefix":"10.1007","volume":"23","author":[{"given":"Brenna C.","family":"Duffy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Nonnemacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhya","family":"Kortagere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"issue":"2","key":"789_CR1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1212\/WNL.56.2.257","volume":"56","author":"N Sacktor","year":"2001","unstructured":"Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, et al. 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