Cannabis and pathogenic mechanisms influencing blood brain barrier function in HIV - people with HIV (PWH) remain vulnerable to central nervous system complications (e.g., neurocognitive impairment)…

Cannabis and pathogenic mechanisms influencing blood brain barrier function in HIV - people with HIV (PWH) remain vulnerable to central nervous system complications (e.g., neurocognitive impairment) despite antiretroviral therapy (art) that suppresses viral replication. While many etiologies of these complications exist, damage to the blood-brain-barrier (BBB), inflammation, and mitochondrial dysfunction are consistently implicated, yet seldom studied simultaneously. PWH also use cannabis more frequently than the general population and recent evidence by our group and others indicates that cannabis may protect PWH from BBB damage by reducing inflammation and promoting mitochondrial homeostasis. The proposed multidisciplinary, translational project will combine a clinical observational study with two preclinical models: a) a technologically advanced brain chip model for BBB and b) personalized EX vivo/in vitro modeling of mitochondrial toxicity in BBB cells to determine the effects of cannabis use on the BBB in PWH. Using this multilevel approach, we will test the hypothesis that cannabis effects on the BBB vary based on patterns of use: moderate use will be associated with beneficial effects, due to the anti-inflammatory properties of cannabis, but chronic daily use will have detrimental effects. In a cohort of PWH and people without HIV (pwoh) across a range of cannabis use from naïve to daily users, we will measure in plasma and cerebrospinal fluid (CSF) a panel of biomarkers that reflect the BBB, inflammation, and mitochondrial dysfunction. These readouts will be correlated with advanced permeability and multicompartment diffusion magnetic resonance imaging that will identify global and regional variations in BBB leakage along with neuronal and glial microstructural properties (aim 1). We will model the BBB using 3D microfluidic cultures of brain endothelial and parenchymal cell subsets to measure the effects of HIV and cannabinoids on BBB permeability, inflammatory gene expression, and markers of mitochondrial function (aim 2). Because responses to HIV and cannabis are often specific to individuals or groups of individuals, we will use monocyte-derived macrophages and sera from the PWH and pwoh in the observational study to determine the effects of cannabis (and HIV) on BBB cellular components (astrocytes and endothelial cells), and on mitochondrial function, inflammatory gene expression, and BBB biomarker gene expression (aim 3). Thus, the proposed project will provide innovative clinical readouts in a unique cohort alongside state-of-the-art modeling of the BBB and personalized investigation of pathogenic mechanisms. This highly innovative, multidisciplinary research proposal is very likely to generate impactful translational knowledge regarding mechanisms of pathogenesis and guide future therapeutic interventions. With our combined clinical and pre-clinical expertise in HIV infection, substance abuse, BBB biology and imaging, and mitochondrial homeostasis, we are uniquely suited to perform the proposed research.