Vaccine and Infectious Disease Division

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The connection of HIV infection to foreskin

Several clinical trials have shown that circumcision partially reduces the risk of sexually transmitted diseases such as HIV. In fact, South Africa now has a national public health campaign supporting voluntary adult male circumcision to decrease the incidence of HIV/AIDS. While clinical trials have shown that circumcision is inversely correlated with risk of HIV acquisition, the mechanism is not fully understood.

The current study aimed to characterize foreskin epithelium, which may make this tissue a target for HIV infection, as HIV is not normally transmitted through the skin. Uncircumcised penises have a skin fold that leaves the inner foreskin tissue moist and exposed to anaerobic bacteria, whereas the outer foreskin remains exposed to air and resembles healthy skin. In collaboration with scientists from Lima, Peru VIDD Research Associate Dr. Maria Lemos, Staff Physician Dr. Shelly Karuna, Assistant Member Dr. Youyi Fong, Associate Member Dr. Raphael Gottardo and Member Dr. Julie McElrath utilized foreskin samples collected during the HVTN 914 clinical trial cohort of 20 men who have sex with men (MSM) from Lima who agreed to undergo elective circumcision.

The inner foreskin contains an influx of CD4+ T cells

Foreskin sections from inner (left) and outer (right) foreskin were stained for CD4 (red), CCR5 (green) and cell nuclei (blue). Whereas the outer foreskin epidermis (E) contains few CD4+ T cells, at the inner foreskin epidermis there are many CD4+ CCR5+ cells. Both inner and outer foreskin have epidermal CD4+ T-cell aggregates (A).

Figure from Lemos M, et al. 2014. PLoS One, 9(9), e108954.

The subjects were HIV seronegative and reported high risk behavior for HIV infection. The authors compared the inner and outer foreskin using immunofluorescent microscopy, and they found evidence of modifications in the inner epidermal integrity proteins, including keratin and tight junctions, which regulate skin permeability. This provides a possible mechanism for how the inner foreskin fold may increase risk of penile HIV entry.

One longstanding hypothesis of why circumcised men have a decreased risk of HIV infection is because inflammatory cells are localized to the foreskin. HIV enters CD4+ T cells by binding to the surface protein CCR5, and the authors were especially interested in differences in CD4+ T-cell density and CCR5 expression between inner and outer foreskin. They immunofluorescently labeled the tissue for CD4 and CCR5 and visualized the cells in the epidermis and dermis (see figure). They found that both inner and outer foreskin have CD4+ T-cell aggregates in the dermis. But in the inner foreskin epidermis, the most external part of the skin, there are increased CCR5+ cells and CD4+ CCR5+ cells. These results suggest the inner foreskin fold provides an inflammatory milieu that could theoretically increase target cells for HIV infection.  

Lemos MP, Lama JR, Karuna ST, Fong Y, Montano SM, Ganoza C, Gottardo R, Sanchez J, McElrath MJ. The Inner Foreskin of Healthy Males at Risk of HIV Infection Harbors Epithelial CD4+ CCR5+ Cells and Has Features of an Inflamed Epidermal Barrier. 2014. PLoS One. 9(9), e108954.

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