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Adv."],"published-print":{"date-parts":[[2026,7,17]]},"abstract":"<jats:p>Despite effective antiretroviral therapy (ART), people with HIV (PWH) are at risk for central nervous system (CNS) abnormalities, including cognitive impairment. B cells and antibodies are key mediators of adaptive immunity in neuroinflammatory disorders and crucial for viral control, but their role in HIV-associated CNS pathology is unknown. Here, we apply multimodal transcriptomic, epigenetic, and B cell receptor profiling of B cells across cerebrospinal fluid (CSF), choroid plexus, and blood from ART-treated PWH and people without HIV, alongside neurocognitive assessments. In ART-suppressed PWH, CSF resting memory B cells exhibit impaired pathogen responsiveness and high antibody gene mutations, suggesting CNS-restricted antigenic adaptation. Choroid plexus B cells exhibit similar transcriptomic immune perturbations despite viral suppression. Notably, CNS-specific B cell molecular alterations are associated with poorer neurocognitive performance. 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