Cannabis use by people with HIV is associated with an anti-inflammatory immunometabolic phenotype in monocyte-derived macrophages

Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naïve/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state. Cannabis use by people with HIV (PWH) is associated with neuroprotective and anti-inflammatory effects, mediated in part by reprogramming the immunometabolism of monocyte-derived macrophages (MDMs). This shift involves a transition from a pro-inflammatory, glycolytic phenotype toward a more anti-inflammatory state characterized by oxidative phosphorylation and altered cytokine expression. In cannabis-Naïve/Low PWH, MDMs exhibit a pro-inflammatory profile that promotes neuroinflammation and mitochondrial damage, resulting in a reduced number of mitochondria. Chronic neuroinflammation contributes to neurodegeneration and the neurocognitive impairments (NCI) that define HIV-Associated Neurocognitive Disorders (HAND). This inflammatory and neurodegeneration profile is reflected by plasma immunometabolic biomarkers including reduced mature BDNF (mBDNF), and elevated GDF15 and soluble TREM2 (sTREM2) levels. Conversely, cannabis use in PWH induces an anti-inflammatory MDM profile that promotes reduced neuroinflammation with increased mitochondrial biogenesis. The reduced neuroinflammation leads to improved neuronal function and reduced NCI, resulting in improved memory, motor and verbal skills, and executive learning. This neuroprotective effect is corroborated by corresponding plasma biomarkers showing increased mBDNF levels, and decreased GDF15 and sTREM2 levels. Collectively, these findings suggest that cannabis use by PWH appears to mitigate neuroinflammation and NCI, with the immunometabolic reprogramming of MDMs likely playing a key mechanistic role. Graphical Methods The HIV Neurobehavioral Research Program (HNRP) donor cohort consisted of people without HIV (PWoH) and people with HIV (PWH) who were either cannabis naïve/low, moderate cannabis users, or daily cannabis users. Peripheral blood mononuclear cells (PBMCs) were isolated from donor blood samples, plated, and allowed to differentiate for two weeks into monocyte-derived macrophages (MDMs) before being tested or treated with THC and then tested. At the same time plasma samples were isolated from each donor and stored for testing. At that point specific dyes were added, and different parameters were measured such as on the CX5 CellInsight Imager or an ELISA and the data was then analyzed.