Y Ganor1, A-S Drillet-Dangeard, M Bomsel. 1. Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS (UMR 8104), Paris, France; INSERM U1016, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France.
Abstract
AIM: Peripheral neurones innervating mucosal epithelia are in direct contact with resident immune cells, including Langerhans cells (LCs). Such neurones secrete the neuropeptide calcitonin gene-related peptide (CGRP) that modulates LCs function. We recently found that CGRP strongly inhibits human immunodeficiency virus type 1 (HIV-1) transmission, by interfering with multiple steps of mucosal LC-mediated HIV-1 transfer, including increased expression of the LC-specific lectin langerin. Herein, we investigated the anti-HIV-1 mechanism of CGRP. METHODS: In the presence of CGRP, HIV-1 transfer from LCs to CD4+ T cells was tested with viral clones using either the HIV-1 co-receptor CCR5 (R5) or CXCR4 (X4). Surface expression of CCR5, CXCR4 and langerin was evaluated by flow cytometry. CGRP secretion by LCs was measured with an enzyme immunoassay. Expression of the multimeric CGRP receptor was examined by quantitative real-time RT-PCR and immuno-fluorescent microscopy. RESULTS: Calcitonin gene-related peptide decreased transfer of HIV-1 R5, but increased that of X4. These opposing effects correlated with decreased CCR5 vs. increased CXCR4 surface expression in LCs. Inhibition of HIV-1 R5 transfer by CGRP involved signal transducer and activator of transcription 4 (STAT4) activation. Both αCGRP and βCGRP were similarly efficient in decreasing HIV-1 R5 transfer and increasing langerin expression. LCs secreted low basal levels of endogenous CGRP, which increased markedly following CGRP treatment. CGRP also increased expression of its cognate receptor in LCs. CONCLUSION: CGRP engages a positive feedback mechanism that would further enhance its anti-HIV-1 activity. This information might be relevant for the therapeutic use of CGRP as a prophylactic agent against HIV-1.
AIM: Peripheral neurones innervating mucosal epithelia are in direct contact with resident immune cells, including Langerhans cells (LCs). Such neurones secrete the neuropeptide calcitonin gene-related peptide (CGRP) that modulates LCs function. We recently found that CGRP strongly inhibits human immunodeficiency virus type 1 (HIV-1) transmission, by interfering with multiple steps of mucosal LC-mediated HIV-1 transfer, including increased expression of the LC-specific lectin langerin. Herein, we investigated the anti-HIV-1 mechanism of CGRP. METHODS: In the presence of CGRP, HIV-1 transfer from LCs to CD4+ T cells was tested with viral clones using either the HIV-1 co-receptor CCR5 (R5) or CXCR4 (X4). Surface expression of CCR5, CXCR4 and langerin was evaluated by flow cytometry. CGRP secretion by LCs was measured with an enzyme immunoassay. Expression of the multimeric CGRP receptor was examined by quantitative real-time RT-PCR and immuno-fluorescent microscopy. RESULTS:Calcitonin gene-related peptide decreased transfer of HIV-1 R5, but increased that of X4. These opposing effects correlated with decreased CCR5 vs. increased CXCR4 surface expression in LCs. Inhibition of HIV-1 R5 transfer by CGRP involved signal transducer and activator of transcription 4 (STAT4) activation. Both αCGRP and βCGRP were similarly efficient in decreasing HIV-1 R5 transfer and increasing langerin expression. LCs secreted low basal levels of endogenous CGRP, which increased markedly following CGRP treatment. CGRP also increased expression of its cognate receptor in LCs. CONCLUSION:CGRP engages a positive feedback mechanism that would further enhance its anti-HIV-1 activity. This information might be relevant for the therapeutic use of CGRP as a prophylactic agent against HIV-1.
Keywords:
CC chemokine receptor 5; CXC chemokine receptor 4; Langerhans cells; calcitonin gene-related peptide; human immunodeficiency virus type 1; signal transducer and activator of transcription 4
Authors: Yi-Lynn Liang; Matthew J Belousoff; Madeleine M Fletcher; Xin Zhang; Maryam Khoshouei; Giuseppe Deganutti; Cassandra Koole; Sebastian G B Furness; Laurence J Miller; Debbie L Hay; Arthur Christopoulos; Christopher A Reynolds; Radostin Danev; Denise Wootten; Patrick M Sexton Journal: ACS Pharmacol Transl Sci Date: 2020-03-20
Authors: Laura Ochoa-Callejero; Josune García-Sanmartín; Pablo Villoslada-Blanco; María Íñiguez; Patricia Pérez-Matute; Elisabet Pujadas; Mary E Fowkes; Rachel Brody; José A Oteo; Alfredo Martínez Journal: J Endocr Soc Date: 2021-01-04