Herpes simplex virus type 2 (HSV-2) infections is one of the driving forces behind the HIV epidemic In sub- Saharan Africa. This is especially true for adolescent/young women who acquire both infections rapidly after sexual debut. We hypothesize that genital inflammation among young women in sub-Saharan Africa is largely driven by HSV-2 acquisition. Our Sp. Aim 1 will determine if HSV-2 acquisition among young African women results in persistent (>1 year) genital inflammation. The primary outcome will be the change in concentrations of the three pro-inflammatory factors MIP-ip, IL-1 a, and IL-8, measured by Luminex assays in cervicovaginal lavage (CVL) samples from adolescent women before and after initiation of sexual activity, and after HSV-2 seroconversion. We will test for other sexually transmitted infections, and for sexual activity by PSA, to determine their relative contribution to genital inflammation. A secondary clinical outcome will be the density of vulvar infiltration with HIV target cells, as measured by absolute densities of CCR5+ T cells, macrophages and dendritic cells (DCs), quantified by immunofluorescence staining vulvar biopsies obtained from women before and after HSV-2 acquisition. We will compare these biopsies to matched control women who are sexually active but remain HSV-2 seronegative. In year 1 we will conduct an exploratory microarray transcriptome study in an ex vivo vulvovaginal explant tissue model of HSV-2 infection. Our Sp Aim 2 will test whether the frequency of HSV-2 reactivation at set point correlates with the degree of inflammatory changes. We will establish a cohort of HSV-2/HIV negative adolescent women in Thika, Kenya. The women who acquire HSV-2 infection will be enrolled into a 60-day intensive study of HSV-2 shedding, during which they self-collect daily genital swabs for HSV-2 detection. The results on this study will define the role of HSV-2 in mucosal priming of young women for HIV acquisition upon exposure, provide insights into the mechanism, and lay foundation for future interventions for HSV-2 such as chemoprophylaxis, microbicides or vaccines.