Cannabidiol prevents mucosal HIV-1 transmission by targeting Langerhans cells, dendritic cells, macrophages and T-cells

Abstract HIV-1 transmission depends on the structure and immune cell composition of mucosal epithelia. Transmission mechanisms involve direct infection of CD4+ T-cells or macrophages, and indirect viral transfer to CD4+ T-cells from Langerhans cells (LCs) or dendritic cells (DCs). LCs-mediated HIV-1 transfer is inhibited by the neuropeptide calcitonin gene-related peptide (CGRP), due to upstream activation in LCs of the transient receptor potential vanilloid 1 (TRPV1) ion channel. Herein, we investigated the potential anti-HIV-1roles of cannabidiol (CBD), the non-psychoactive compound in marijuana, which has well-described immunosuppressive functions and principally activates TRPV1 over its cognate CB1 and CB2 receptors. We found that via TRPV1 activation, CBDinhibitsin-vitroinfection of mucosal HIV-1 cellular targets. Specifically, CBD inhibits macrophages HIV-1 direct infection, and CD4+ T-cells HIV-1 direct infection or upon viral transfer from LCsand DCs. Moreover, inhibition of macrophages infection and LCs-mediated HIV-1 transfer involves secreted CGRP.Importantly, CBD also blocks early events of HIV-1 transmission ex-vivo in human inner foreskin tissues, namely formation of epidermal LC-T-cell conjugates and resulting CD4+ T-cells infection. Altogether, CBD inhibits infection of all HIV-1 cellular targets, and commercial CBD products might be repositioned as novel HIV-1 pre-exposure prophylaxis, namely ‘CBD PrEP'.