Differential Compartmentalization of HIV-Targeting Immune Cells in Inner and Outer Foreskin Tissue

Abstract

Ex vivo foreskin models have demonstrated that inner foreskin is more susceptible to HIV-1 infection than outer foreskin. In the present study we characterized the compartition of HIV-1 target cells and quantified these cells in the epidermis and dermis of inner and outer foreskins using immunohistochemistry and flow cytometry. Our data showed that the epidermis of the inner foreskin was more enriched with CD4+ T cells and Langerhans cells (LCs), with the co-expression of CCR5 and α4β7 receptors, than the outer foreskin. Interestingly, the vast majority of CD4+ T cells and LCs expressed CCR5, but not CXCR4, indicating that the inner foreskin might capture and transmit R5-tropic HIV strains more efficiently. In addition, lymphoid aggregates, composed of T cells, macrophages and dendritic cells (DCs) in the dermis, were closer to the epithelial surface in the inner foreskin than in the outer foreskin. As dendritic cells are able to capture and pass HIV particles to susceptible target cells, HIV may be able to more efficiently infect the inner foreskin by hijacking the augmented immune communication pathways in this tissue. After the inoculation of HIV-1 particles in a foreskin explant culture model, the level of p24 antigen in the supernatant from the inner foreskin was slightly higher than that from the outer foreskin, although this difference was not significant. The present study is the first to employ both CCR5 and α4β7 to identify HIV target cells in the foreskin. Our data demonstrated that the inner foreskin was more enriched with HIV target immune cells than the outer foreskin, and this tissue was structured for efficient communication among immune cells that may promote HIV transmission and replication. In addition, our data suggests the R5-tropism of HIV sexual transmission is likely shaped through the inherent receptor composition on HIV target cells in the mucosa.

Langerhans cells and sexual transmission of HIV and HSV

“…Langerhans cells derived from vagina, ectocervix, foreskin, glans, and fossa navicularis have all been shown to express the HIV entry receptor CD4 and coreceptor CCR5 and have consequently long been known to support productive infection of HIV, which occurs via neutral fusion of the virus envelope with the DC plasma membrane and is mediated via the virus envelope glycoprotein gp160. Interestingly, one study showed that LCs in the inner foreskin express higher levels of CCR5 than that in the outer foreskin, and higher CCR5 expression has also been observed on LCs in the glans compared to the fossa navicularis . Similar findings have been shown in the colorectal tract where rectal macrophages have been shown to express higher levels of CCR5 than colonic macrophages and indicate that specific anogenital sites may differ in their susceptibility to R5 HIV infection.…”

“…Langerhans cells are consistently observed and present in close proximity to the surface in both, but there is inconsistency as to their observed relative abundance in each site; 1 study reports more LCs in the outer foreskin, 55 3 show more in the inner foreskin, [56][57][58] and at least 2 report no difference. 59,60 The penile glans and fossa navicularis are far less studied but both have been observed to contain LCs, which are more abundant in the former. 61 Furthermore, LCs in the glans penis have been observed to extend their dendrites towards the epithelial surface, 55 and have consequently long been known to support productive infection of HIV, which occurs via neutral fusion of the virus envelope with the DC plasma membrane and is mediated via the virus envelope glycoprotein gp160.…”

Characterization of CD4+ T cell subsets and HIV susceptibility in the inner and outer foreskin of Ugandan men

“…Our virus entry analysis does not take into account the important role that local dendritic cells (DCs) may play in mediating HIV acquisition. DCs derived from the inner foreskin demonstrate greater apical migration, more efficient environmental sampling, conjugate formation, and enhanced chemokine production; all of these factors enhance T cell trafficking to the inner foreskin and/or increased susceptibility to cellular HIV entry . Furthermore, virus entry is only the first step in virus replication and does not necessarily imply productive infection, which may be enhanced in more metabolically active cells, such as Th17 cells .…”

“…The major co‐receptor for sexually transmitted HIV strains is CCR5, and CCR5 + CD4 + T cells are enriched in the inner foreskin . Expression of the mucosal/tissue‐homing integrins α4β7 and α4β1 on CD4 + T cells may also enhance cellular HIV susceptibility, although it is unknown whether the same applies to cells expressing other integrins/addressins, such as CD103 (αEβ7) and cutaneous lymphocyte antigen (CLA) .…”

Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

“…The role of epithelial cells as one of the cellular targets of HIV infection is not clearly resolved. Foreskin epithelial cells express HIV coreceptors (15) and when the cells are infected with herpes simplex virus 2, the cells internalize HIV virions (16). Although the virions do not replicate, they can be transferred to lymphocytes by coculturing (17).…”