Inflammasome formation and interleukin-1β secretion are reduced in peripheral blood monocytes from HIV+ cannabis users.

Chronic systemic inflammation remains a defining feature of human immunodeficiency virus (HIV) infection, partly driven by the translocation of microbial-derived products, including toll-like receptor 4 agonist lipopolysaccharide, from the gut, which is a well established HIV reservoir. These products activate peripheral blood monocytes, leading to the secretion of proinflammatory cytokines, particularly interleukin-1β (IL-1β), which exacerbates systemic inflammation. Cannabis and its bioactive constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol, exhibit immune-modulating properties, yet their effects on innate immune pathways in HIV remain poorly defined. Here, we investigated the impact of cannabis use and individual cannabinoids, THC and cannabidiol, on toll-like receptor 4-induced ASC-incorporating inflammasome activation, IL-1β secretion, and caspase-1 activity in monocytes derived from HIV-negative and HIV-positive individuals. We hypothesized that cannabis use and cannabinoid treatment impair inflammasome-mediated inflammation in HIV+ individuals, potentially mitigating IL-1β-driven immune activation. Our results show that inflammasome formation was reduced in both HIV+ marijuana (cannabis use status, MJ)- and HIV+MJ+ (MJ: cannabis use) derived monocytes compared with HIV- derived monocytes. Despite this, HIV+MJ- monocytes secreted more IL-1β than HIV- monocytes, whereas HIV+MJ+ monocytes secreted IL-1β at levels comparable to those of HIV- cells. Both THC and cannabidiol suppressed inflammasome formation and IL-1β secretion in a concentration-dependent manner, with THC producing a greater magnitude of reduction in caspase-1 activity in HIV- monocytes. Cannabis use by HIV+ individuals lowered IL-1β secretion by peripheral blood monocytes compared with that of non-cannabis-using HIV+ donors, implicating an inhibitory role in immune activation. These findings support the therapeutic potential of cannabinoids in reducing HIV-associated systemic inflammation. SIGNIFICANCE STATEMENT: Cannabis use reduced inflammasome activation and interleukin-1β (IL-1β) release in human immunodeficiency virus (HIV)+ monocytes. HIV+ cannabis users showed IL-1β levels comparable to HIV- individuals, whereas HIV+ cannabis nonusers displayed elevated levels of IL-1β secretion. The combination of reduced ASC-incorporating inflammasome formation but elevated IL-1β in HIV+ nonusers suggests involvement of noncanonical IL-1β maturation pathways.