{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:48:51Z","timestamp":1782452931402,"version":"3.54.5"},"reference-count":117,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS124477"],"award-info":[{"award-number":["R01 NS124477"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 MH134776"],"award-info":[{"award-number":["R01 MH134776"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 NS137986"],"award-info":[{"award-number":["R21 NS137986"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 AI117970"],"award-info":[{"award-number":["P30 AI117970"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    HIV\u2010associated neurocognitive disorders (HAND) remain prevalent in people with HIV (PWH) despite effective antiretroviral therapy, suggesting that persistent immune activation contributes to ongoing neurological dysfunction. Maladaptive trained immunity (TRIM), long\u2010term innate immune reprogramming characterized by sustained inflammatory responses, metabolic rewiring, and epigenetic remodeling, has been proposed as a sustaining mechanism. We performed single\u2010nucleus RNA\u2010seq and ATAC\u2010seq on post\u2010mortem brain from PWH with HIV\u2010associated dementia (HAD) or asymptomatic neurocognitive impairment (ANI) and compared these data with published HIV\u2010uninfected (PWoH) datasets. In PWH versus PWoH, glia, led by microglia, showed enrichment of innate immune signaling and upregulation of inflammatory mediators including\n                    <jats:italic>NLRP3<\/jats:italic>\n                    ,\n                    <jats:italic>TLR2<\/jats:italic>\n                    , and\n                    <jats:italic>TLR4<\/jats:italic>\n                    . In parallel, glia showed coordinated cholesterol remodeling, with efflux transporter and apolipoprotein upregulation alongside\n                    <jats:italic>LDLR<\/jats:italic>\n                    downregulation, and partial microglial glycolytic reprogramming (\n                    <jats:italic>PFKFB3<\/jats:italic>\n                    ,\n                    <jats:italic>HK2<\/jats:italic>\n                    ,\n                    <jats:italic>PGK1<\/jats:italic>\n                    upregulation). Chromatin accessibility profiling showed concordant gains at inflammatory, cholesterol regulatory (notably\n                    <jats:italic>RXRA<\/jats:italic>\n                    and\n                    <jats:italic>APOE<\/jats:italic>\n                    ), and glycolytic loci. The HAD versus ANI comparison revealed selective reorganization rather than uniform amplification, with increased lipid scavenger receptor accessibility in oligodendrocytes and reduced accessibility at cholesterol efflux and glycolytic loci. Neurons exhibited predominantly bystander epigenetic changes. Three features distinguish this pattern from chronic inflammation alone and align it with trained immunity hallmarks: concordant transcriptional and chromatin\u2010level priming at inflammatory loci, parallel rewiring of glycolytic and cholesterol metabolism, and persistence despite long\u2010term viral suppression. These multiomic data are consistent with maladaptive trained immunity sustaining neuroinflammation in HAND, though functional validation is required.\n                  <\/jats:p>","DOI":"10.1002\/glia.70191","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:32:11Z","timestamp":1782451931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single\u2010Nucleus Multiomic Analysis Reveals Immune\u2013Metabolic Reprogramming Consistent With Maladaptive Trained Immunity in\n                    <scp>HIV<\/scp>\n                    \u2010Associated Neurocognitive Disorders"],"prefix":"10.1002","volume":"74","author":[{"given":"Siera","family":"Martinez","sequence":"first","affiliation":[{"name":"The George Washington University School of Medicine and Health Sciences  Washington Washington, DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anelia","family":"Horvath","sequence":"additional","affiliation":[{"name":"The George Washington University School of Medicine and Health Sciences  Washington Washington, DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Johnson","sequence":"additional","affiliation":[{"name":"The George Washington University School of Medicine and Health Sciences  Washington Washington, DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Pushkarsky","sequence":"additional","affiliation":[{"name":"The George Washington University School of Medicine and Health Sciences  Washington Washington, DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Dubrovsky","sequence":"additional","affiliation":[{"name":"The George Washington University School of Medicine and Health Sciences  Washington Washington, DC 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8593-0770","authenticated-orcid":false,"given":"Michael","family":"Bukrinsky","sequence":"additional","affiliation":[{"name":"The George Washington University School of Medicine and Health Sciences  Washington Washington, DC 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