Genin, H. | bioRxiv Science

bioRxiv2026

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

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-1 roles of cannabidiol (CBD), the non-psychoactive compound in Cannabis sativa, which has well-described immunosuppressive functions and principally activates TRPV1 over its cognate CB1 and CB2 receptors. We found that via TRPV1 activation, CBD inhibits in-vitro infection 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 LCs and 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.

microbiology↗

bioRxiv2024

CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients

Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage and cytokine storm. One unexplored hub in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients, and restore to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analogue SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatment with GRRP and/or SAX is enough to block SARS-CoV-2 productive infection of Calu3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients, by directly inhibiting SARS-CoV-2 infection. Hence, CGRP-based interventions could be harnessed for management of COVID-19. Brief summaryPulmonary levels of the neuropeptide CGRP are increased in critical COVID-19 patients, and could clear virus by directly inhibiting SRAS-CoV-2 infection of bronchial epithelia cells.

microbiology↗