Molecular Signatures of HIV‐Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV

HIV-associated neurological complications remain a major concern in people living with HIV (PWH), even under effective viral suppression with combination antiretroviral therapy (cART), underscoring unresolved mechanisms driving HIV-related neurodegeneration. To address this gap, we used HIV-1-infected human cerebral organoids (hCOs) containing microglia as a physiologically relevant three-dimensional model of the central nervous system (CNS) and validated key findings in the brain region of simian immunodeficiency virus (SIV)-infected, cART-treated rhesus macaque model. Integrated single-nucleus RNA sequencing with ATAC-seq (multi-omics), identifies cell-type-specific alterations in dual innate immune-driven inflammatory signaling pathways across neural and glial populations in hCOs. Microglia were preferentially infected and activated, initiating IL-17A-mediated cascades involving IFN-γ/STAT1, CEBPB, and NF-κB signaling. These pathways converged with cGAS-STING and Notch-NEURL1 signaling, both associated with neuroinflammation and synaptic dysfunction. cART suppressed viral replication, reduced IL-17A-mediated neuroinflammation, improved mitochondrial function, and restored synaptic gene expression. Collectively, these findings identify dysregulation of IL-17A, STAT1, CEBPB, and cGAS-STING signaling as key molecular drivers of HIV-associated neuroinflammation. They also establish a potential mechanistic link between IL-17A signaling and microglial remodeling, providing a translational framework for the development of CNS-targeted therapies in PWH.