The long term goal of this renewal is to better understand local and systemic immune responses to human papillomavirus (HPV) infection in its natural setting of the cervix early in its course as well as in states of persistence or clearance. The first aim of the study is to examine the local immune response in the natural history of cervical HPV infection in young women by comparing changes in the local cervical cytokine milieu, specifically interferon (IFN)-gamma, interleukin (IL)-12, IL-2, IL-10 and IL-4, in association: a) persistence, b) clearance of initial and/or c) secondary infections, and d) development of SIL. The second aim is to examine systemic response to HPV specifically cytotoxic T cell response to HPV 16 infections in association with the four HPV states described above. Four groups of women will be recruited for the study: 1) women with a long history of persistent HPV infection, 2) women with secondary HPV type infections, 3) adolescent and young women with evidence of initial HPV infection, 4) women with a long history of persistent HPV negativity (control group). Examinations for women from the first three groups seen every 4 months will include samples for: HPV DNA, cytology, cervical cell cytokine analysis using RT-PCR, C. trachomatis, N. gonorrhea, herpes simplex virus, bacterial vaginosis, and peripheral blood CTL assays on women with HPV 16 infection. The control group (HPV negative) will have similar examinations every 6 months and have HPV serology to virus-like particles (VLP) to characterize HPV exposure not defined by repeated HPV testing. The understanding of both local and systemic immune responses to initial and subsequent HPV infections may be key in vaccine or therapeutic developments.