Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has recently been associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission in a manner not accounted for by plasma HIV-1 RNA load(1). We hypothesize that compared to cervicovaginal fluid (CVF) from healthy individuals, BV CVF induces an elevated pro-inflammatory and pro-chemotactic response in cells of the foreskin which may facilitate transmission. Because foreskin epithelial cells are one of the first cells to encounter HIV during female-to-male transmission, we propose to compare the effects of healthy vs. BV CVF on primary epithelial cells cultured from human foreskin tissues. These studies will take advantage of the extensive experience the PI’s UCSF mentor has had in culturing primary epithelial cells from genital tract tissue, and examining the response of these cells to genital secretions(2). We propose to expose epithelial cells cultured from foreskin tissue to healthy and BV CVF, and to conduct microarray and Luminex studies to assess the global response of these cells to CVF and to determine whether BV CVF elicits a more proinflammatory response. Because there have been recent reports that epithelial cells from the female genital tract can support productive HIV infection in a manner increased by HIV-enhancing factors from seminal plasma(3-5), in the second part of this grant we will investigate a non-mutually exclusive alternative mechanism by which BV CVF might promote transmission: by promoting productive infection of foreskin epithelial cells. Overall, these studies will lead to a better understanding of why BV associates with increased female-to-male HIV transmission.