20,21 This superficial Gefitinib datasheet layer is also easily sloughed, so an intact layer is unlikely to be found after sexual intercourse or to play a key role in protection against HIV infection. Another argument against this primary role is that the keratinization of the oral mucosa is relatively non-existent, yet oral transmission of HIV remains the most inefficient route of transmission.22 Beyond the keratin layers, the skin’s barrier function relies on other components such as intercellular

junctions. These cell-to-cell junctions serve to regulate cell and epidermal growth, but also to protect the integrity of the epidermis.23,24 Expression of these proteins can vary between epithelial strata in different areas of the body, which may influence how well protected

some areas are when compared to others. Early work in our laboratory has shown subtle differences in protein expression PKC inhibitor patterns of foreskin and cervical tissues, which may contribute to differences in HIV movement between the female and male genital tract. We have also investigated skin characteristics relating to barrier function and permeability and found that these may lend insight into how the presence of the foreskin may lead to greater HIV transmission (data not shown). Female-to-male HIV sexual transmission is the least well-described route of transmission,

perhaps because of its relative inefficiency. However, many men initially aminophylline acquire HIV from heterosexual sex with infected female partners, and they in turn infect others unknowingly. Male circumcision has only been shown to protect the men themselves against HIV acquisition, not their female partners.6 The lack of a fundamental understanding in how circumcision works to prevent against infections precludes our ability to understand why it protects in certain routes and not others. In 2007, the Merck Adenovirus 5 (Ad5)-HIV-1 gag/nef/pol vaccine (STEP) trial was halted because of significantly increased HIV acquisition rates in vaccine when compared to placebo recipients.25 Furthermore, uncircumcised vaccinated men were at up to a fourfold increased risk for HIV infection relative to the other cohorts. Longer-term follow-up showed that only circumcision status (and not baseline Ad5 titers, as initially believed) correlated with HIV incidence rates. The reasons for these findings remain unknown even after several years of ad hoc studies. Overly simplistic theories, such as keratin thicknesses or sheer numbers of resident target cells, do not sufficiently explain these observations.