The 2025 Conference on Retroviruses and Opportunistic Infections (CROI) showcased advances in understanding neuropsychiatric complications among people with HIV (PWH). This review synthesizes key findings related to central nervous system (CNS) reservoirs, neuropathogenesis, and biomarkers of brain health. Emerging data underscore the persistence of HIV in brain tissues despite antiretroviral therapy (ART), with compartmentalization occasionally observed in the spinal cord and brain, and evidence suggesting that HIV-infected cells may contribute to chronic inflammation in the CNS. Single-cell and epigenetic profiling of cerebrospinal fluid cells revealed immune dysregulation in myeloid and B cells, suggesting ongoing CNS dysfunction during suppressive ART. Longitudinal neuroimaging and cognitive studies reinforced that incomplete or unstable HIV suppression correlates with worse brain outcomes. Notably, higher blood phosphorylated tau 217 and systemic inflammation predicted cognitive decline in aging PWH. Promising therapeutic avenues included observations that glucagon-like peptide-1 receptor agonists, such as semaglutide, improve visuospatial performance in PWH and cannabinoid receptor 2 agonists reduced neuroinflammatory pathways in preclinical models. Additionally, early initiation of ART was associated with normalization of brain volumes and attenuation of neuronal injury markers. Together, these findings highlight the complexity of neuro-HIV interactions and underscore the need for targeted interventions to protect brain health in PWH.