Single‐Nucleus Multiomic Analysis Reveals Immune–Metabolic Reprogramming Consistent With Maladaptive Trained Immunity in <scp>HIV</scp> ‐Associated Neurocognitive Disorders

HIV-associated 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-term innate immune reprogramming characterized by sustained inflammatory responses, metabolic rewiring, and epigenetic remodeling, has been proposed as a sustaining mechanism. We performed single-nucleus RNA-seq and ATAC-seq on post-mortem brain from PWH with HIV-associated dementia (HAD) or asymptomatic neurocognitive impairment (ANI) and compared these data with published HIV-uninfected (PWoH) datasets. In PWH versus PWoH, glia, led by microglia, showed enrichment of innate immune signaling and upregulation of inflammatory mediators including NLRP3, TLR2, and TLR4. In parallel, glia showed coordinated cholesterol remodeling, with efflux transporter and apolipoprotein upregulation alongside LDLR downregulation, and partial microglial glycolytic reprogramming (PFKFB3, HK2, PGK1 upregulation). Chromatin accessibility profiling showed concordant gains at inflammatory, cholesterol regulatory (notably RXRA and APOE), 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-level priming at inflammatory loci, parallel rewiring of glycolytic and cholesterol metabolism, and persistence despite long-term viral suppression. These multiomic data are consistent with maladaptive trained immunity sustaining neuroinflammation in HAND, though functional validation is required.