Full-length native CGRP neuropeptide and its stable analogue SAX, but not CGRP peptide fragments, inhibit mucosal HIV-1 transmission

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 reported that CGRP strongly inhibits human immunodeficiency virus type 1 (HIV-1) infection, by suprresing Langerhans cells (LCs)-mediated HIV-1 transfer to T-cells during trans-infection. To understand the requirements for CGRP receptor (CGRP-R) activation during inhibition of HIV-1 transmission, we here investigated the anti-HIV-1 activities of full-length native CGRP and its recently developed stable analogue SAX, as well as several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. We show that SAX significantly inhibits LCs-mediated HIV-1 trans-infection but with lower potency than CGRP, while all CGRP peptide fragments tested have no effect. In addition, CGRP readily enters the epithelial compartment of mucosal tissues and does not modify the distribution and density of mucosal immune cells. In-vivo, a single CGRP treatment in humanized mice, before vaginal challenge with high-dose HIV-1, restricts the increase in plasma viral load and maintains higher CD4+ T-cell counts. Together, our results call for the optimization and design of CGRP analogues and agonists, which could be harnessed for prevention of mucosal HIV-1 transmission.