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Our previous studies have implicated hypoxia\u2010inducible factor\u20101 alpha (HIF\u20101\u03b1) as a central regulator of HIV\u20101 Tat\u2010mediated amyloid production in astrocytes, which are further released via astrocyte\u2010derived extracellular vesicles (ADEVs), inducing synaptodendritic injury and Alzheimer's\u2010like pathology in naive mice. Based on this premise, we hypothesized that ADEVs carrying HIF\u20101\u03b1\u2010targeting small interfering RNA (siRNA) would alleviate HIV\u20101\u2010induced Alzheimer's\u2010like pathology and neurodegeneration in CD34+ NSG HIV\u2010infected humanized mice. Intranasally administered mCherry\u2010TSG101\u2010tagged ADEVs in mice demonstrated efficacy of brain delivery, especially to the hippocampus and cortex. In CD34+ NSG mice infected with HIV\u20101, intranasal delivery of HIF\u20101\u03b1 siRNA\u2010loaded ADEVs suppressed HIF\u20101\u03b1, reduced amyloid precursor protein (APP), A\u03b2moC64, A\u03b2 fibrils, and hyperphosphorylated tau (pTau), dampened glial activation as indicated by reduced GFAP and IBA1 expression, and partially restored synaptic proteins, which were dysregulated due to HIV\u20101 infection. Trends of improvement were also observed in behavioural deficits in spatial memory, anxiety\u2010like behaviour, and sensorimotor gating induced by HIV\u20101. These findings position HIF\u20101\u03b1 as a pivotal mediator of HIV\u2010associated Alzheimer's\u2010like pathology and neurodegeneration in the CD34+ NSG mice and underscore the promising role of ADEV\u2010mediated HIF\u20101\u03b1 siRNA delivery as a non\u2010invasive therapeutic strategy for HAND.<\/jats:p>","DOI":"10.1002\/jev2.70191","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T11:04:20Z","timestamp":1762859060000},"source":"Crossref","is-referenced-by-count":6,"title":["HIF\u20101 Targeting Intervention Renders Protection From Alzheimer's\u2010Like Pathology in a Humanized Mice Model of HIV Infection"],"prefix":"10.1002","volume":"14","author":[{"given":"Sudipta","family":"Ray","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine University of Nebraska Medical Center  Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine University of Nebraska Medical Center  Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya T.","family":"Chemparathy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine University of Nebraska Medical Center  Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanta K.","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine University of Nebraska Medical Center  Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8941-985X","authenticated-orcid":false,"given":"Susmita","family":"Sil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience, College of Medicine University of Nebraska Medical Center  Nebraska USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11481-009-9152-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2010.03.073"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1807"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000551"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.761"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181e7b66e"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2009.11.004"},{"issue":"1","key":"e_1_2_10_9_1","first-page":"22","article-title":"Advanced in Immunological Monitoring of HIV Infection: Profile of Immune Cells and Cytokines in People Living With HIV\u20101 in Benin","volume":"25","author":"Assogba Y. 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