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

Abstract

Problem 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. Method of study 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. Results 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). Conclusion 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.

The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

“…Although these cells typically home towards the gut via the CCR6-CCL20 chemotactic axis, this is impaired in ART-suppressed, HIVinfected individuals as there is a decreased production of CCL20 by enterocytes in response to IFN-γ secretion by Th1 cells as well as IL-10 and TGF-β secretion by Tregs [183,184]. Recently, Th17 cells were found to be enriched in the inner foreskin of uninfected men compared to the outer foreskin [185]. The dynamics of these cells in this tissue during HIV infection however are yet to be established.…”

“…It is important to note that despite the restoration of the gut Th22 cell population following ART intervention, these cells are unable to functionally compensate for the depletion of Th17 cells that persists [182]. Recently, Th22 cells were found to be enriched in the outer foreskin of uninfected men compared to the inner foreskin [185]. The role of these cells in this tissue during HIV infection however remains to be explored.…”

Impact of Endemic Infections on HIV Susceptibility in Sub-Saharan Africa

“…Since the foreskin tissues are not mucosal in the traditional sense because they lack mucus-secreting capacity and are keratinized, it is possible that the effects of endemic mucosal infections on penile HIV susceptibility might be quite different to vaginal and rectal tissues. In addition to the anatomical differences, differences in CD4+ T cell trafficking to the foreskin versus the female genital tissues may also explain differences in HIV susceptibility of men versus women [48, 55].…”

“…In keeping with this, S. mansoni -infected women with a higher parasite burden demonstrated elevated expression of the mucosal homing integrin α4β7 on blood CD4+ T cells [226], which would be expected to home these CD4 cells to the gut and cervical mucosa. However, this integrin does not appear to home T cells to the foreskin, the predominant site of HIV acquisition in heterosexual men from SSA, since the predominant integrin expressed on T cells in foreskin tissues is cutaneous lymphocyte antigen (CLA) [48]. The latter could at least partly explain the differential impact of S. mansoni infection on HIV susceptibility in women versus men.…”

Protocol for a randomized clinical trial exploring the effect of antimicrobial agents on the penile microbiota, immunology and HIV susceptibility of Ugandan men

“…Based on previously defined pseudovirus entry parameters into inner foreskin-derived CD4 + T cells [32], a sample size of 25 participants per group will provide statistical power of 80% to identify clinical approaches that reduce virus entry by ≥ 33% (based on a median virus entry of 15.1% into inner foreskin-derived CD4 + T cells), which is the efficacy threshold that we have deemed as sufficient to move a strategy forward.…”