Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda

HIV susceptibility is heterogeneous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibility may be mediated by immune alterations in the genital mucosa. However, immune correlates of HIV-exposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n=20) and unexposed control (n=57) men undergoing elective circumcision. Swabs were assayed for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T cell subsets from foreskin tissue were assessed by flow cytometry. HESN foreskins had elevated α-defensins (3027 vs. 1795 pg/ml, p=0.011) and HIV-neutralizing IgA (50.0 vs. 13.5% of men, p=0.019). Foreskin tissue from HESN men contained a higher density of CD3 T cells (151.9 vs. 69.9 cells/mm(2), p=0.018), but a lower proportion of these were Th17 cells (6.12 vs. 8.04% of CD4 T cells, p=0.007), and fewer produced TNFα (34.3 vs. 41.8% of CD4 T cells, p=0.037; 36.9 vs. 45.7% of CD8 T cells, p=0.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFα production, in combination with HIV-neutralizing IgA and α-defensins, may represent a protective immune milieu at a site of HIV exposure.