Enhanced cellular responses and environmental sampling within inner foreskin explants: implications for the foreskin's role in HIV transmission.

The decrease in HIV acquisition after circumcision suggests a role for the foreskin in HIV transmission. However, the mechanism leading to protection remains undefined. Using tissue explant cultures we found that Langerhans cells (LCs) in foreskin alter their cellular protein expression in response to external stimuli. Furthermore, we observe that upon treatment with TNF-alpha, tissue-resident LCs became activated and that stimulatory cytokines can specifically cause an influx of CD4+ T-cells into the epithelial layer. Importantly, both of these changes are significant in the inner, but not outer, foreskin. In addition, we find that LCs in the inner foreskin have increased ability to sample environmental proteins. These results suggest differences in permeability between the inner and outer foreskin and indicate that HIV target cells in the inner foreskin have increased interaction with external factors. This increased responsiveness and sampling provides novel insights into the underlying mechanism of how circumcision can decrease HIV transmission.

Overexpression of simian virus 40 small-T antigen blocks centrosome function and mitotic progression in human fibroblasts.

Recombinant adenoviruses that express high levels of the simian virus 40 (SV40) small-t (ST) antigen have been used to study the requirement for ST to drive cell cycle proliferation of confluent human diploid fibroblasts. This occurs when either large-T (LT) antigen or serum is added to provide a second signal. While cells readily completed S phase in these experiments, they were found to accumulate with 4N DNA content. Cellular and nuclear morphology, as well as the biochemical status of cyclin B complexes, showed that these cells entered mitosis but were blocked prior to mitotic metaphase. The defect appears to reflect an inability of cells overexpressing ST to form organized centrosomes that duplicate and separate normally during the cell cycle and, therefore, the absence of a mitotic spindle. The ability of ST to bind protein phosphatase 2A was required for this pattern, suggesting that altered phosphorylation of key centrosomal components may occur when ST is overexpressed. Although the possible significance of ST effects on the centrosome cycle is not fully understood, these findings suggest that ST could influence chromosomal instability patterns that are a hallmark of SV40-transformed cells and LT expression.