Basic Science Award

Mucosal epithelia are the first tissue sites of contact of HIV with the human body during the course of infection, and these play a critical role in determining its success in establishing systemic infection. We have shown that experimental disruption of tight junctions of mucosal epithelium may facilitate HIV transmission across mucosal epithelia by paracellular penetration, which requires no viral replication and, therefore, antiretroviral therapy would not be expected to block such transmission. Human papillomavirus (HPV) is the most common sexually transmitted agent of the mucosal epithelium. We have also shown that the tight junctions in HPV-infected epithelial anal lesions are disrupted, suggesting that HPV dissemination within the mucosal epithelium may increase the risk of HIV transmission. It is well documented that oncogenic type HPV-infected anogenital epithelial lesions contain elevated levels of proinflammatory cytokines, including interferon gamma (IFN-_) and tumor necrosis factor-alpha (TNF-_), which may dissociate tight junctions and open paracellular spaces. We hypothesize that HPV-associated upregulation of IFN-_ and TNF-_ expression within the HPV-infected anogenital mucosal epithelium disrupts epithelial junctions, leading to paracellular HIV penetration. Accordingly, the specific aims of this proposal are: (1) Determine paracellular HIV transmission across HPV-infected anal epithelial lesions with disrupted tight junctions. (2) Investigate the roles of IFN-_ and TNF-_ in disruption of tight junctions and HIV transmission across HPV-infected anal mucosal epithelium. The data obtained from this proposal will greatly advance current knowledge about the mechanisms of HV transmission across mucosal epithelia and will open new avenues for designing drugs that may specifically reduce or block HIV passage across these epithelia.