ABSTRACT The number of older people living with HIV-1 (PLWH) has increased dramatically in the past decade in the US and other Western countries. PLWH experience similar health problems as the general population of older individuals, but at an increased frequency and severity, which is consistent with accentuated aging. Extensive evidence, including studies in the PI’s laboratory, demonstrated amyloid pathology in HIV-1 infection, including dysregulations at the blood-brain barrier (BBB) interface. HIV-infected brains have advanced amyloidopathy, which is characterized by increased amyloid beta (Aβ) deposition mostly in the perivascular space when compared to age-matched controls. Among HIV-associated non-AIDS comorbidities, cerebrovascular diseases, including ischemic stroke, are particularly frequent. While the mechanisms of these conditions are not fully understood, the present application focuses on the role of enhanced procoagulant environment and amyloidopathy as critically important underlying factors. Our current proposal is built on the most exciting and clinically relevant findings resulting from the previous funding cycle, which explored the role of extracellular vesicles (EV) in Aβ transfer to neural progenitor cells (NPCs), and their impaired neurogenesis. We mapped EV cargo proteins and identified Serpine-1 (also known as plasminogen activator inhibitor 1, PAI-1), in various crossroads of neurodegenerative pathways relevant to HIV-associated neurocognitive decline (HAND). This is a paramount discovery because Serpine-1 plays a role in both the generation of a procoagulant environment, and the production and accumulation of Aβ. Therefore, we hypothesize that a procoagulant environment driven by elevated Serpine-1 levels contributes to increased risk of ischemic events, delayed post-ischemic recovery, and enhanced amyloidopathy in HIV-infected brain. Specific mechanisms evaluated in this application include dysregulation of the BBB and enhanced amyloidopathy (Aim 1), reprograming mitochondria and induction of inflammatory responses (Aim 2), and impaired differentiation and migration of NPCs (Aim 3). The complex role of Serpine-1 in HIV-1 infection in the context of both ischemic events and amyloidopathy has been overlooked in the literature, making our proposal conceptually novel. Moreover, this research has potential to generate new therapeutic targets and strategies in aging and HIV-1 infection, especially in prevention and treatment of cerebrovascular comorbidities, including ischemic events.