Chronic inflammation affects people living with HIV (PHW) and leads to the development of HIV-related and non-HIV-related comorbidities including metabolic syndrome, cardiovascular disease, opportunistic infections, HIV-associated neurocognitive disorders (HAND), among others. HAND is of special concern because it affects 20-50% of HIV-positive patients despite the efficacy of modern combined antiretroviral therapy (cART) and improved quality of life, and there are no effective therapies available. Some mechanistic aspects associated with HAND include increased peripheral monocyte and macrophage activation; secretion of pro-inflammatory cytokines, chemokines, and viral proteins; invasion of HIV-infected cells, and proinflammatory factors into the central nervous system (CNS); infection of microglia; activation of CNS resident cells; and neuronal injury. The specific roles of peripheral monocytes/macrophages (Mφs) in the neuropathogenesis of HIV are not fully understood. Our research project aims to determine how dysregulation of the innate immune responses in Mφs contribute to inflammation, neuronal dysfunction, and cognitive impairment in PWH. We are establishing human 3D brain organoids co-cultured with patient-derived monocytes, to model immune cell invasion to the CNS and study monocyte-neuron interactions in vitro. Our approach includes a combination of several techniques including: flow cytometry, immunoassays, single-cell RNA sequencing, and CRISPR/Cas9, to characterize monocyte populations, neuronal damage markers and disrupted signaling mechanisms. We will expand the brain organoids techniques to study other neurodegenerative diseases, such as Alzheimer’s disease, and develop additional 3D cultures, as part of our collaborations.