title: HIV-1 efficient entry in inner foreskin is mediated by elevated CCL5/RANTES that recruits T cells and fuels conjugate formation with Langerhans cells.
abstract: Male circumcision reduces acquisition of HIV-1 by 60%. Hence, the foreskin is an HIV-1 entry portal during sexual transmission. We recently reported that efficient HIV-1 transmission occurs following 1 h of polarized exposure of the inner, but not outer, foreskin to HIV-1-infected cells, but not to cell-free virus. At this early time point, Langerhans cells (LCs) and T-cells within the inner foreskin epidermis are the first cells targeted by the virus. To gain in-depth insight into the molecular mechanisms governing inner foreskin HIV-1 entry, foreskin explants were inoculated with HIV-1-infeceted cells for 4 h. The chemokine/cytokine milieu secreted by the foreskin tissue, and resulting modifications in density and spatial distribution of T-cells and LCs, were then investigated. Our studies show that in the inner foreskin, inoculation with HIV-1-infected cells induces increased CCL5/RANTES (1.63-fold) and decreased CCL20/MIP-3-alpha (0.62-fold) secretion. Elevated CCL5/RANTES mediates recruitment of T-cells from the dermis into the epidermis, which is blocked by a neutralizing CCL5/RANTES Ab. In parallel, HIV-1-infected cells mediate a bi-phasic modification in the spatial distribution of epidermal LCs: attraction to the apical surface at 1 h, followed by migration back towards the basement membrane later on at 4 h, in correlation with reduced CCL20/MIP-3-alpha at this time point. T-cell recruitment fuels the continuous formation of LC-T-cell conjugates, permitting the transfer of HIV-1 captured by LCs. Together, these results reveal that HIV-1 induces a dynamic process of immune cells relocation in the inner foreskin that is associated with specific chemokines secretion, which favors efficient HIV-1 entry at this site.
authors: Mucosal Entry of HIV-1 and Mucosal Immunity, Cell Biology and Host Pathogen Interactions Department, Cochin Institute, CNRS (UMR 8104), Paris, France.
authors: Zhicheng
authors: Z
authors: Zhou
authors: Nicolas
authors: N
authors: Barry de Longchamps
authors: Alain
authors: A
authors: Schmitt
authors: Marc
authors: M
authors: Zerbib
authors: Marie-Cécile
authors: MC
authors: Vacher-Lavenu
authors: Morgane
authors: M
authors: Bomsel
authors: Yonatan
authors: Y
authors: Ganor
mesh_terms: D002450:Cell Communication / Q000276:immunology / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000276:immunology; D002944:Circumcision, Male; D052816:Foreskin / Q000276:immunology / Q000821:virology*; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D053586:Virus Internalization
chemical_list: C108355:CCL20 protein, human; C483024:CCL5 protein, human; D054418:Chemokine CCL20; D018946:Chemokine CCL5