The Inner Foreskin of Healthy Males at Risk of HIV Infection Harbors Epithelial CD4+ CCR5+ Cells and Has Features of an Inflamed Epidermal Barrier

Abstract

Male circumcision provides partial protection against multiple sexually transmitted infections (STIs), including HIV, but the mechanisms are not fully understood. To examine potential vulnerabilities in foreskin epithelial structure, we used Wilcoxon paired tests adjusted using the false discovery rate method to compare inner and outer foreskin samples from 20 healthy, sexually active Peruvian males who have sex with males or transgender females, ages 21–29, at elevated risk of HIV infection. No evidence of epithelial microtrauma was identified, as assessed by keratinocyte activation, fibronectin deposition, or parakeratosis. However, multiple suprabasal tight junction differences were identified: 1) inner foreskin stratum corneum was thinner than outer (p = 0.035); 2) claudin 1 had extended membrane-bound localization throughout inner epidermis stratum spinosum (p = 0.035); 3) membrane-bound claudin 4 was absent from inner foreskin stratum granulosum (p = 0.035); and 4) occludin had increased membrane deposition in inner foreskin stratum granulosum (p = 0.042) versus outer. Together, this suggests subclinical inflammation and paracellular transport modifications to the inner foreskin. A setting of inflammation was further supported by inner foreskin epithelial explant cultures secreting higher levels of GM-CSF (p = 0.029), IP-10 (p = 0.035) and RANTES (p = 0.022) than outer foreskin, and also containing an increased density of CCR5+ and CD4+ CCR5+ cells (p = 0.022). Inner foreskin dermis also secreted more RANTES than outer (p = 0.036), and had increased density of CCR5+ cells (p = 0.022). In conclusion, subclinical changes to the inner foreskin of sexually active males may support an inflammatory state, with availability of target cells for HIV infection and modifications to epidermal barriers, potentially explaining the benefits of circumcision for STI prevention.

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

“…This may reflect a gradual decline in HIV target cells within remaining penile tissue, as effector T cells have been shown to be slow to clear a site of previous infection, and are enriched in tissue sites for months after antigen becomes undetectable in the skin [70]. In vitro studies also suggest that target cell availability contributes to the efficacy of male circumcision, as the inner aspect of the foreskin contains a comparatively high density of HIV target cells [15, 33–35]. Male circumcision may reduce HIV susceptibility by reducing penile inflammation and HIV target cell availability.…”

“…Additionally, we found no correlations between IL-8 concentration and date of swab collection, suggesting that variability in swab storage time due to the relatively short duration of the trial (August 2003- November 2006) cannot account for the differences in IL-8 levels observed when examining the impact of circumcision on cytokine levels. It is possible that associations with other cytokines may have been missed due to low analyte concentration, explaining why cytokines observed to be released ex vivo from foreskin explants were not detectable in swabs in this study [33, 35, 69]. …”

“…One hypothesis is that circumcision reduces genital inflammation and immune activation, either through the prevention of viral STIs [31], the reduction of inflammatory anaerobic bacteria [32], or through other mechanisms yet to be defined, which in turn this reduces the density of potential target cells for HIV. This hypothesis is supported by ex vivo experiments demonstrating that the inner aspect of the foreskin has an increased density of HIV target cells [33–35] and more efficient virus transfer from Langerhans cells to local CD4 T cells [15] than the outer aspect, which is contiguous with the shaft skin that remains after circumcision. These observations suggest that the intact foreskin constitutes an immunologically activated tissue milieu that promotes target cell recruitment and dendritic cell maturation [36–38].…”

Common urological problems in children: prepuce, phimosis, and buried penis

“…These changes may support a subclinical inflammatory state in uncircumcised men, with availability of target cells for HIV infection, and potentially account for the benefits of circumcision in STD prevention. 34 All the trials were performed in Africa, with a much higher prevalence of HIV. Education about use of condoms and safe sex practice was relatively primitive compared with Hong Kong.…”

Circumcision Status is Not Associated with Condom Use and Prevalence of Sexually Transmitted Infections Among Young Black MSM

“…Biological evidence suggests that the penile foreskin is rich in CD4? target cells thereby creating a convenient “target” for the attachment of free virus during sex as an insertive partner [5]. A recent review examining the sexual risk behavior of Black MSM concluded that evidence was insufficient to support the effectiveness of circumcision to prevent HIV acquisition among Black MSM [4].…”