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

Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibilitymay bemediated by immune alterations in the genitalmucosa.However, immune correlates ofHIVexposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n1/420) and unexposed control (n1/457) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets fromforeskin tissuewere assessed by flowcytometry.HESNforeskins had elevated a-defensins (3,027 vs. 1,795 pgml1,P1/40.011) and HIV-neutralizing IgA(50.0 vs. 13.5%ofmen,P1/40.019).Foreskin tissue fromHESNmen contained a higherdensityofCD3 T cells (151.9 vs. 69.9 cellsmm2, P1/40.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04%of CD4 Tcells, P1/40.007), and fewer produced tumor necrosis factor a (TNFa) (34.3 vs. 41.8% of CD4 Tcells, P1/40.037; 36.9 vs. 45.7%of CD8 T cells, P1/40.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFa production, in combinationwithHIV-neutralizing IgAand a-defensins,may represent a protective immunemilieu at a site ofHIVexposure.