Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda

Abstract

Individual susceptibility to HIV is heterogeneous, but the biological mechanisms explaining differences are incompletely understood. We hypothesized that penile inflammation may increase HIV susceptibility in men by recruiting permissive CD4 T cells, and that male circumcision may decrease HIV susceptibility in part by reducing genital inflammation. We used multi-array technology to measure levels of seven cytokines in coronal sulcus (penile) swabs collected longitudinally from initially uncircumcised men enrolled in a randomized trial of circumcision in Rakai, Uganda. Coronal sulcus cytokine levels were compared between men who acquired HIV and controls who remained seronegative. Cytokines were also compared within men before and after circumcision, and correlated with CD4 T cells subsets in foreskin tissue. HIV acquisition was associated with detectable coronal sulcus Interleukin-8 (IL-8 aOR 2.26, 95%CI 1.04–6.40) and Monokine Induced by γ-interferon (MIG aOR 2.72, 95%CI 1.15–8.06) at the visit prior to seroconversion, and the odds of seroconversion increased with detection of multiple cytokines. Coronal sulcus chemokine levels were not correlated with those in the vagina of a man’s female sex partner. The detection of IL-8 in swabs was significantly reduced 6 months after circumcision (PRR 0.59, 95%CI 0.44–0.87), and continued to decline for at least two years (PRR 0.29, 95%CI 0.16–0.54). Finally, prepuce IL-8 correlated with increased HIV target cell density in foreskin tissues, including highly susceptible CD4 T cells subsets, as well as with tissue neutrophil density. Together, these data suggest that penile inflammation increases HIV susceptibility and is reduced by circumcision.

The penile microbiota of Black South African men: relationship with human papillomavirus and HIV infection

“…The best evidence to date for a potential role of the penile microbiome in sexually transmitted infections (STIs) and HIV acquisition have come from studies examining medical circumcision [5,6]. Male circumcision reduces the risk of HPV and HIV infection in men [7][8][9][10][11].…”

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

“…As might be expected, given the increased dampness of the inner foreskin surface, cytokine and chemokine levels were higher here than on the surface of the outer foreskin. This may be important for several reasons, first and foremost because the ability to detect IL‐8 and other chemokines on the foreskin surface has been directly linked to an increased risk of HIV acquisition . The mechanism of increased susceptibility appears to be the induction of sub‐clinical inflammation and remodeled tight junctions within the inner foreskin, possibly in response to higher local levels of anaerobic gram‐negative bacteria, with subsequent recruitment of activated CD4 + T cell subsets .…”

“…Penile circumcision reduces the risk of HIV acquisition by almost two thirds in heterosexual men, and although the World Health Organization has adopted penile circumcision as a HIV prevention strategy in high prevalence regions, logistical and socio‐cultural barriers hinder effective implementation . The efficacy of penile circumcision in HIV prevention implies that the foreskin is a primary site of HIV acquisition during penile‐vaginal sex, and in keeping with this, the foreskin is rich in potential HIV target cells, and higher specific chemokine levels (IL‐8 and MIG) in the foreskin prepuce are associated with increased HIV acquisition risk . Therefore, a better understanding of the immunopathogenesis of HIV acquisition at this tissue site may help to develop new prevention strategies for men who opt to remain uncircumcised.…”

Vaginal epidermal dendritic cells: defense against HIV-1 or a safe haven?

“…Much less is known of LCs, a unique subset of DCs in mucosal squamous epithelium and skin epidermis, and their specific variants. In addition to DCs and their subsets, microenvironments such as chemokine levels in mucosal tissues correlate with HIV acquisition in men (8). Making progress in the identification of new DC subsets exposed to HIV-1 during the early stages of infection can ultimately either open new therapeutic opportunities to block the infection or represent unexpected obstacles to eradication.…”