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The inflammasome-pyroptosis axis coordinates an inflammatory type of regulated lytic cell death that is underpinned by the caspase-activated pore-forming gasdermin proteins. The mechanisms driving neuronal pyroptosis were investigated herein in models of HAND, using multi-platform molecular and morphological approaches that included brain tissues from persons with HAND and simian immunodeficiency virus (SIV)-infected non-human primates as well as cultured human neurons.<\/jats:p>\n               <jats:p>Neurons in the frontal cortices from persons with HAND showed increased cleaved gasdermin E (GSDME), which was associated with \u03b2-III tubulin degradation and increased HIV levels. Exposure of cultured human neurons to the HIV-encoded viral protein R (Vpr) elicited time-dependent cleavage of GSDME and Ninjurin-1 (NINJ1) induction with associated cell lysis that was inhibited by siRNA suppression of both proteins. Upstream of GSDME cleavage, Vpr exposure resulted in activation of caspases-1 and 3. Pretreatment of Vpr-exposed neurons with the caspase-1 inhibitor, VX-765, reduced cleavage of both caspase-3 and GSDME, resulting in diminished cell death. To validate these findings, we examined frontal cortical tissues from SIV-infected macaques, disclosing increased expression of GSDME and NINJ1 in cortical neurons, which was co-localized with caspase-3 detection in animals with neurological disease. Thus, HIV infection of the brain triggers the convergent activation of caspases-1 and -3, which results in GSDME-mediated neuronal pyroptosis in persons with HAND.<\/jats:p>\n               <jats:p>These findings demonstrate a novel mechanism by which a viral infection causes pyroptotic death in neurons while also offering new diagnostic and therapeutic strategies for HAND and other neurodegenerative disorders.<\/jats:p>","DOI":"10.1093\/brain\/awad375","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T19:51:44Z","timestamp":1699300304000},"page":"717-734","source":"Crossref","is-referenced-by-count":26,"title":["Caspase cleavage of gasdermin E causes neuronal pyroptosis in HIV-associated neurocognitive disorder"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0458-7019","authenticated-orcid":false,"given":"Jason P","family":"Fernandes","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, AB T6G 2R3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G","family":"Branton","sequence":"additional","affiliation":[{"name":"Department of Medicine (Neurology), University of Alberta , Edmonton, AB T6G 2R7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A","family":"Cohen","sequence":"additional","affiliation":[{"name":"Laboratory of Human Retrovirology, Institut de Recherches Cliniques Montreal (IRCM) , Montreal, QC H2W 1R7 , Canada"},{"name":"Department of Microbiology, Infectiology and Immunology, Universit\u00e9 de Montr\u00e9al , Montreal, QC H3C 3J7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit","family":"Koopman","sequence":"additional","affiliation":[{"name":"Department of Virology, Biomedical Primate Research Centre (BPRC) , Rijswijk 2280 GH , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivanela","family":"Kondova","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Biomedical Primate Research Centre (BPRC) , Rijswijk 2280 GH , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin B","family":"Gelman","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Neurobiology, University of Texas Medical Branch , Galveston, TX 77555-0569 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5131-9711","authenticated-orcid":false,"given":"Christopher","family":"Power","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, AB T6G 2R3 , Canada"},{"name":"Department of Medicine (Neurology), University of Alberta , Edmonton, AB T6G 2R7 , 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