Abstract
Recent evidence that circumcision decreases HIV infection in heterosexual men by 50-60% has focused research on the foreskin as a target of HIV infection. In this review article, we discuss potential mechanisms underlying the circumcision effect and re-examine the assumption that the foreskin is the principle penile HIV infection site. HIV target cells are present in the foreskin epithelium, but are also found in the epithelia of the penile shaft, glans/corona, meatus and urethral introitus. Sexually transmitted infections (STIs) can affect any of these sites and increase susceptibility to HIV acquisition by eroding the protective epithelial layer and by attracting and activating HIV target cells in the epithelium. The moist subpreputial cavity, which encompasses the entire penile tip in most uncircumcised men including the glans, meatus and urethral introitus, plays an important role in STI acquisition. Circumcised men have a lower rate of STIs that infect not only the foreskin but also other distal penile sites, especially the urethra. Likewise, the foreskin may trap HIV and HIV-infected cells after intercourse thereby increasing the risk of HIV acquisition not only through the inner foreskin but also other sites covered by the foreskin. The subpreputial cavity also hosts a unique microbiome that may also play a role in HIV infection. We hypothesize that the penile urethra may be the primary HIV acquisition site in circumcised men and possibly also in non-circumcised men because of the presence of superficial HIV target cells and a high incidence of STIs at this site. Both innate and adaptive immune defense mechanisms are operative in the lower male genital region. The penile urethral mucosa contains accumulations of IgA(+) plasma cells and T lymphocytes and may provide a responsive target for future mucosal vaccines to prevent HIV sexual transmission.