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Calcitonin gene-related peptide inhibits Langerhans cell-mediated HIV-1 transmission.

Abstract : Upon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene-related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC-T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1-infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1.
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Yonatan Ganor, Anne-Sophie Drillet-Dangeard, Lucia Lopalco, Daniela Tudor, Giuseppe Tambussi, et al.. Calcitonin gene-related peptide inhibits Langerhans cell-mediated HIV-1 transmission.. Journal of Experimental Medicine, Rockefeller University Press, 2013, 210 (11), pp.2161-70. ⟨10.1084/jem.20122349⟩. ⟨inserm-01068714⟩

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