This is a new Program Project application in response to RFA-HD-00- 006 to establish a Women's HIV Pathogenesis program at the University of Washington in collaboration the University of Rochester and the University of Nairobi, Kenya. The central Program these is to explore the hypothesis that the female genital tract is a separate virological compartment from blood. As such, viral application in the genital compartment may be influenced by several factors including the host's hormonal status (i.e., menses), and both viral and microbiological cofactors that could have an important influence on the evolution of HIV- 1 (i.e., generation of viral diversity), re-seeding of the blood compartment with potentially drug-resistant, and disease pathogenesis both within the genital tract (changes from favorable to unfavorable microbiological flora) and systemically (HIV-1 disease progression). Understanding these gender-specific HIV-1 factors may provide additional insight into the control of both vertical and horizontal transmission of HIV-1. To accomplish the central Program theme, we will use three different cohorts of HIV-1-infected women recruited at the three collaborating institutions. The research activities of the Program Project will be accomplished through three Cores and three Research Projects. The infrastructure will reside within an Administrative Core (Core A) located at the University of Washington, a Clinical Core (Core B) and a Laboratory Core (Core C). Both internal and external advisory committees will review the Program's research progress and report to the Principal Investigator, Dr. Coombs. Since our hypothesis is that genital tract inflammation represents a continuum as defined by local vaginitis (bacterial vaginosis), to cervicitis (cytomegalovirus), to endometritis (microbial) and ultimately to pelvic inflammatory disease, each of the three research Projects are designed to capture this continuum. In Project I (HIV-1 shedding and evolution), we will characterize subjects for shedding of HIV-1, CMV and HSV-2, and definitively establish, through viral phylogenetic typing that HIV-1- re-emerges from the genital tract to re-infect the blood compartment in subjects that receive stable anti- retroviral therapy. In Project II (CMV co-shedding) we will show that CMV is an independent viral co-factor for HIV-1 shedding, whether CMV shedding from the cervix represents reactivation or re-infection, and that the suppression of CMV using valganciclovir can decrease HIV- 1 genital shedding. In Project III( Bacterial Vaginosis), we will show the effect of bacterial vaginosis as a local co-factor for HIV-1 shedding, how this local abnormal microbiological flora contributes to HIV-1 shedding through local cytokine-mediated mechanisms, and that anti-microbial treatment of bacterial vaginosis in both anti-retroviral treated and untreated women results in decreased HIV-1 genital shedding. Taken together, these studies will provide important comparative data to the male genital tract shedding of HIV-1 and may have implications for both the vertical and horizontal transmission of HIV-1.
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