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

Abstract

Biological mechanisms of foreskin HIV acquisition are poorly defined. The inner foreskin is preferentially infected in explant models, so we hypothesized that this site would be enriched for HIV-susceptible CD4+ T cells and proinflammatory/chemoattractant cytokines. A total of 42 HIV-uninfected Ugandan men without genital symptoms provided foreskin tissues and swabs at the time of elective penile circumcision. The immune phenotype of foreskin-derived CD4+ T cells and entry of a CCR5-tropic HIV pseudovirus was characterized, and specific cytokine levels assayed by multiplexed chemiluminescent ELISA. Unexpectedly, outer foreskin CD4+ T cells more frequently expressed CCR5 (median 29.2% vs 22.9%, P=0.01) and CD69 (median 36.5% vs 15%, P<0.01), and on a per-cell basis, HIV entry was higher. However, overall CD4+ T cell density was approximately twofold higher in the inner foreskin, and several highly susceptible T cell subsets were increased at this site, including Th17 cells (20.0% vs 14.1%, P=0.0021). Specific pro-inflammatory cytokine levels were also higher on the inner foreskin surface (IL-17, IL-8, RANTES and IL-1β; all P<0.05). There was marked heterogeneity in CD4+ T cell populations and immune milieu between inner and outer foreskin tissues. Despite higher per-cell viral entry into CD4+ T cells from the outer foreskin, the higher target cell density and enriched pro-inflammatory cytokines of the inner foreskin suggest that this may be a preferential site for HIV acquisition.