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

Frontiers in Immunology

Anette Sams¹  Lars Edvinsson¹  Gabriel Siracusano²  Lucia Lopalco³  Yonatan Ganor⁴  Jammy Mariotton⁴  Emmanuel Cohen⁴  Morgane Bomsel⁴  Alexis Sennepin⁴  Francesca Sanvito⁵  Marc Zerbib⁶  Nicolas Barry Delongchamps⁶ 

[1] Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Copenhagen, Denmark;Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Hospital, Milan, Italy;Immunobiology of HIV, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy;Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Institut Cochin, Université de Paris, INSERM U1016, CNRS UMR8104, Paris, France;Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Hospital, Milan, Italy;Urology Service, GH Cochin-St Vincent de Paul, Paris, France;

关键词: CGRP;    HIV-1;    humanized BLT mice;    Langerhans cells;    SAX;    STAT4;   

DOI  :  10.3389/fimmu.2021.785072

来源: DOAJ

【 摘 要 】

BackgroundThe 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 in-vitro and mucosal HIV-1 transmission ex-vivo. This inhibition is mediated via 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.MethodsWe tested the capacity of CGRP to inhibit HIV-1 infection in-vivo 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 in-vitro and mucosal HIV-1 transmission in human mucosal tissues ex-vivo.ResultsA 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 in-vitro, but with lower potency. This inhibition is mediated via 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.ConclusionOur 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 for HIV-1 prevention.

【 授权许可】

Unknown