The impact of substance use on the role of T cells in HIV CNS reservoir seeding, persistence, and neuropathogenesis

About This Grant

Cannabis use is high in PLWH, ~25-35% of PLWH report cannabis consumption. Cannabinoids have been shown to have anti-inflammatory properties in humans and animal models. Heavy cannabis use in PLWH on ART is associated with decreased levels of activated T cells in peripheral blood. The two main cannabinoids present in cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC, the psychoactive component of cannabis, is a partial agonist for cannabinoid receptors CB1 and CB2. CB1 is primarily expressed in the brain while CB2 is reportedly expressed in immune cells, including CD4+ T cells. THC exposure modulates human CD4+ T cell gene expression and in animal models skews immune responses towards a Th2 phenotype and increases CD4+ T cell production of anti-inflammatory and immunosuppressive cytokines. CBD has anti-inflammatory and antioxidant effects without the psychoactive properties of THC. CBD exposure has been shown to suppress T cell proliferation, T cell production of IL-2 and IFN-γ production in T cells. Cannabinoid treatment has also been shown to suppress neuroinflammation in animal models of Alzheimer’s disease and multiple sclerosis. Importantly, in non-human primates (NHP) cannabinoid treatment reduced SIV-induced neuroinflammation. Based on these immunomodulatory properties of cannabinoids, we hypothesize that cannabinoids impact HIV infection and persistence in the CNS. Currently, it is not known how cannabis use impacts the phenotype of CD4+ T cells in the brain and their relative abundance and distribution. Therefore, as part of this project we will evaluate the effect of cannabinoids on the natural homeostasis of human T cells in the brain. We will then assess the impact of cannabinoids on the seeding of HIV infection in CD4+ T cells in the brain, the establishment of HIV latency in brain CD4+ T cells, and the efficacy of latency reversal agents to induce HIV expression in CD4+ T cells in the brain under ART-suppression.