This proposal describes a 5-year training program for the development of an independent researcher in the area of reproductive infectious diseases, specifically genital herpes infections in women. This award would provide the applicant valuable didactic training and human and animal research experience from a multidisciplinary mentoring team. An important contributor to the epidemic spread of herpes simplex virus type 2 (HSV-2) is its high frequency of asymptomatic shedding in the genital tract, as transmission of the virus usually occurs during these periods of subclinical reactivation. Therefore, an improved understanding of the risk factors associated with HSV-2 reactivation and shedding are urgently needed. In addition, it is important to improve our understanding of the pathomechanisms associated with HSV-2 reactivation. As hormonal contraceptives are used by more than 100 million women worldwide and bacterial vaginosis is a very common cause of vaginal symptoms, even modest associations with genital shedding of HSV-2 would result in substantial attributable risks for transmission of the virus. Therefore, this research will assess: 1. The effects of hormonal contraceptive use, either oral contraceptive pills or depo-medroxyprogesterone, on daily genital tract shedding of HSV-2 compared to women who do not use hormonal contraceptives in a natural history study of 102 women 2. The effects of asymptomatic bacterial vaginosis on the daily genital tract shedding of HSV-2 by evaluating shedding frequency before and after treatment of bacterial vaginosis in 30 women 3. The effects of exogenous sex steroids on the capacity of HSV-specific T lymphocytes to inhibit HSV reactivation in sensory neurons and subsequent shedding on epithelial surfaces in a murine model.
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