Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission

• Published in: Frontiers in immunology 2021-12, Vol.12, p.785072-785072
• Main Authors: Mariotton, Jammy, Sams, Anette, Cohen, Emmanuel, Sennepin, Alexis, Siracusano, Gabriel, Sanvito, Francesca, Edvinsson, Lars, Delongchamps, Nicolas Barry, Zerbib, Marc, Lopalco, Lucia, Bomsel, Morgane, Ganor, Yonatan
• Format: Article
• Language: English
• Subjects: Animals; Calcitonin Gene-Related Peptide - pharmacology; Calcitonin Gene-Related Peptide - therapeutic use; CGRP; Dipeptides - pharmacology; Disease Models, Animal; Female; Healthy Volunteers; HEK293 Cells; HIV Infections - diagnosis; HIV Infections - prevention & control; HIV Infections - transmission; HIV Infections - virology; HIV-1; HIV-1 - isolation & purification; HIV-1 - pathogenicity; humanized BLT mice; Humans; Immunology; Langerhans cells; Life Sciences; Mice; Mucous Membrane - drug effects; Mucous Membrane - immunology; Mucous Membrane - virology; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Primary Cell Culture; Quinazolines - pharmacology; SAX; STAT4; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - virology; Tissue Culture Techniques
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.785072

The vasodilator neuropeptide calcitonin gene-related peptide (CGRP) plays both detrimental and protective roles in different pathologies. CGRP is also an essential component of the neuro-immune dialogue between nociceptors and mucosal immune cells. We previously discovered that CGRP is endowed with anti-viral activity and strongly inhibits human immunodeficiency virus type 1 (HIV-1) infection, by suppressing Langerhans cells (LCs)-mediated HIV-1 trans-infection and mucosal HIV-1 transmission . This inhibition is mediated activation of the CGRP receptor non-canonical NFκB/STAT4 signaling pathway that induces a variety of cooperative mechanisms. These include CGRP-mediated increase in the expression of the LC-specific pathogen recognition C-type lectin langerin and decrease in LC-T-cell conjugates formation. The clinical utility of CGRP and modalities of CGRP receptor activation, for inhibition of mucosal HIV-1 transmission, remain elusive. We tested the capacity of CGRP to inhibit HIV-1 infection in humanized mice. We further compared the anti-HIV-1 activities of full-length native CGRP, its metabolically stable analogue SAX, and several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. These agonists were evaluated for their capacity to inhibit LCs-mediated HIV-1 trans-infection and mucosal HIV-1 transmission in human mucosal tissues . A single CGRP intravaginal topical treatment of humanized mice, followed by HIV-1 vaginal challenge, transiently restricts the increase in HIV-1 plasma viral loads but maintains long-lasting higher CD4+ T-cell counts. Similarly to CGRP, SAX inhibits LCs-mediated HIV-1 trans-infection , but with lower potency. This inhibition is mediated CGRP receptor activation, leading to increased expression of both langerin and STAT4 in LCs. In contrast, several N-terminal and N+C-terminal bivalent CGRP peptide fragments fail to increase langerin and STAT4, and accordingly lack anti-HIV-1 activities. Finally, like CGRP, treatment of human inner foreskin tissue explants with SAX, followed by polarized inoculation with cell-associated HIV-1, completely blocks formation of LC-T-cell conjugates and HIV-1 infection of T-cells. Our results show that CGRP receptor activation by full-length CGRP or SAX is required for efficient inhibition of LCs-mediated mucosal HIV-1 transmission. These findings suggest that formulations containing CGRP, SAX and/or their optimized agonists/analogues could be harnessed fo