Translational and cross-species studies of the impact of cannabis use and HIV on mitochondrial homeostasis in brain macrophages

About This Grant

Summary/Abstract 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, mitochondrial dysfunction and inflammation 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 mitochondrial damage by improving metabolic homeostasis and reducing inflammation through triggering receptor expressed on myeloid cells (TREM) 2. Moreover, this mechanism may be more important as PWH age, with the average age of PWH currently being >55. This proposed multidisciplinary, translational project will combine a clinical observational study with cellular and in vivo preclinical models to determine the effects of cannabis use on TREM2-mnediated changes in mitochondrial function in the brain in PWH. The preclinical models will include a) personalized ex vivo/in vitro modeling of mitochondrial toxicity in brain macrophages and neurons, and b) a mouse model for HIV-induced neurotoxicity (Eco-HIV) and age-related neuropathogenesis (TREM2*R47H). Using this multilevel approach, we will test the hypothesis that cannabis effects on TREM2-mediated changes in brain mitochondrial homeostasis vary based on patterns of use: moderate use will be associated with beneficial effects, due to the TREM2 promoting and anti-inflammatory properties of cannabis, but chronic daily use will have detrimental effects. In a cohort of aged (>50 years old) PWH 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 mitochondrial homeostasis, TREM2 function, and inflammation. These readouts will be correlated with neurocognitive assessments and PET imaging for TSPO, a marker of neuroinflammation associated with mitochondrial function (Aim 1). We will model brain macrophages using personalized ex vivo cultures of monocyte derived microglia collected from Aim 1 study participants and culture these cells with neurons to identify mechanisms of mitochondrial dysfunction (Aim 2). Using a cross-species approach, we will investigate how different precise doses of cannabinoids interact with HIV and TREM2 variants to affect mitochondrial homeostasis in wild-type and TREM2*R47H mice infected with EcoHIV (Aim 3). 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, imaging, and mitochondrial homeostasis, we are uniquely suited to perform the proposed research.