Background:  Recent clinical trials of medical male circumcision (MMC) for HIV prevention demonstrated that over half of incident HIV infections in uncircumcised heterosexual men are acquired across the foreskin. However, some uncircumcised men do not readily acquire HIV despite prolonged virus exposure through an infected spouse. We hypothesized that this decreased susceptibility to HIV might be related to the abundance and/or function of T cell subsets within the foreskin.

Methods:  Foreskin tissues were obtained from consenting men who were enrolled in the Rakai Community Cohort Study (RCCS) and who opted to undergo MMC at a surgical clinic in Rakai, Uganda. Sexual behavior and partner data, including partner HIV status, were available through the longstanding RCCS. HIV status of the female partner was confirmed on the day of circumcision. Techniques were established to isolate foreskin T cells from surgical tissues, and ex vivo stimulation followed by intracellular cytokine staining was used to examine: CD4⁺ T cell co-expression of CCR5; the frequency of Th17 cells and regulatory T cells (Treg); the capacity of T cells to produce inflammatory cytokines tumor necrosis factor-α and interferon-γ (IFNγ); and HIV-specific T cell responses. There was rigorous blinding of lab personnel performing all immune assays.

Results:  We enrolled 72 men who reported to be in a monogamous relationship with an HIV^– spouse, and 21 HIV exposed, sero-negative (HESN) men who reported regular unprotected sex with an HIV-infected partner despite counseling and the provision of free condoms. There was no difference in the frequency of HIV-specific CD8⁺ T cell responses in blood or foreskin between HESN men and unexposed controls, and CD4⁺ T cell co-expression of CCR5 was similar. The proportion of Th17 cells, a highly HIV-susceptible T cell subset that is present at a high frequency in the foreskin compared to blood, was substantially lower in the foreskin of HESN men compared to controls (3.8 vs 6.7%, p = 0.009). In addition, foreskin T cell production of the pro-inflammatory cytokine IFN-γ was reduced in HESN (29.3% vs 40.4%, p = 0.006).

Conclusions:  T cell production of the inflammatory cytokine IFN-γ and the frequency of Th17 cells were much lower in the foreskin of HESN men compared to HIV unexposed men, suggesting that these factors may represent important immune correlates of reduced HIV susceptibility.