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.

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

“…Langerhans cells (LCs) in the epidermis of the stratified squamous anogenital mucosa are a target cell for productive infection by both HSV-2 and HIV-1 (17)(18)(19)(20). They are major cell targets for HIV-1 in the uninflamed epidermis, despite constituting only 1-2% of epidermal cells, and they extend their processes superficially into its upper layers to form a cellular network in contact with each other.…”

“…They are major cell targets for HIV-1 in the uninflamed epidermis, despite constituting only 1-2% of epidermal cells, and they extend their processes superficially into its upper layers to form a cellular network in contact with each other. They have been shown to take up HIV-1 in vaginal and foreskin explants ex vivo (18,19) and also appear to be a target for SIV in macaque models (21). HSV-1/2 also infect the keratinocytes.…”

Human/Simian Immunodeficiency Virus Transmission and Infection at Mucosal Sites

“…This area is at risk for HIV transmission. Again, the risk of transmission is greater if penile ulcers due to other STDs are present Ganor et al, 2010;Ma et al, 2011;Rothaeusler et al, 2012;Zhou et al, 2011). Mechanisms have been investigated for HIV-1 transmission across human foreskin organ cultures Ganor et al, 2010;Zhou et al, 2011) and for penile SIV transmission in rhesus macaques Rothaeusler et al, 2012) (see next section).…”

“…Again, the risk of transmission is greater if penile ulcers due to other STDs are present Ganor et al, 2010;Ma et al, 2011;Rothaeusler et al, 2012;Zhou et al, 2011). Mechanisms have been investigated for HIV-1 transmission across human foreskin organ cultures Ganor et al, 2010;Zhou et al, 2011) and for penile SIV transmission in rhesus macaques Rothaeusler et al, 2012) (see next section). Of note, in human foreskin explants, virus transmission occurred only through the inner, not the outer, surface of the foreskin, consistent with the concept that it is the mucosal inner surface that is most vulnerable to HIV transmission Ganor et al, 2010;Zhou et al, 2011).…”

“…Mechanisms have been investigated for HIV-1 transmission across human foreskin organ cultures Ganor et al, 2010;Zhou et al, 2011) and for penile SIV transmission in rhesus macaques Rothaeusler et al, 2012) (see next section). Of note, in human foreskin explants, virus transmission occurred only through the inner, not the outer, surface of the foreskin, consistent with the concept that it is the mucosal inner surface that is most vulnerable to HIV transmission Ganor et al, 2010;Zhou et al, 2011). In male macaques, penile exposure to two sequential 5-min high-dose exposures by immersion in phosphate-buffered saline containing SIV mac251 resulted in only about 50% transmission, about half as efficient as vaginal challenge with the same dose in female macaques .…”