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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Study Section
Special Emphasis Panel (ZHD1-DSR-R (06))
Program Officer
Reichelderfer, Patricia
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University of Washington
Schools of Medicine
United States
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Gianella, Sara; Marconi, Vincent C; Berzins, Baiba et al. (2018) Genital HIV-1 Shedding With Dolutegravir (DTG) Plus Lamivudine (3TC) Dual Therapy. J Acquir Immune Defic Syndr 79:e112-e114
Bull, Marta E; Legard, Jillian; Tapia, Kenneth et al. (2014) HIV-1 shedding from the female genital tract is associated with increased Th1 cytokines/chemokines that maintain tissue homeostasis and proportions of CD8+FOXP3+ T cells. J Acquir Immune Defic Syndr 67:357-64
Kantor, Rami; Bettendorf, Daniel; Bosch, Ronald J et al. (2014) HIV-1 RNA levels and antiretroviral drug resistance in blood and non-blood compartments from HIV-1-infected men and women enrolled in AIDS clinical trials group study A5077. PLoS One 9:e93537
Mitchell, Caroline; Balkus, Jennifer E; McKernan-Mullin, Jennifer et al. (2013) Associations between genital tract infections, genital tract inflammation, and cervical cytobrush HIV-1 DNA in US versus Kenyan women. J Acquir Immune Defic Syndr 62:143-8
Coleman, Jenell S; Mwachari, Christina; Balkus, Jennifer et al. (2013) Effect of the levonorgestrel intrauterine device on genital HIV-1 RNA shedding among HIV-1-infected women not taking antiretroviral therapy in Nairobi, Kenya. J Acquir Immune Defic Syndr 63:245-8
Mitchell, Caroline; Balkus, Jennifer E; Fredricks, David et al. (2013) Interaction between lactobacilli, bacterial vaginosis-associated bacteria, and HIV Type 1 RNA and DNA Genital shedding in U.S. and Kenyan women. AIDS Res Hum Retroviruses 29:13-9
Bull, Marta E; Heath, Laura M; McKernan-Mullin, Jennifer L et al. (2013) Human immunodeficiency viruses appear compartmentalized to the female genital tract in cross-sectional analyses but genital lineages do not persist over time. J Infect Dis 207:1206-15
Balkus, Jennifer E; Mitchell, Caroline; Agnew, Kathy et al. (2012) Detection of hydrogen peroxide-producing Lactobacillus species in the vagina: a comparison of culture and quantitative PCR among HIV-1 seropositive women. BMC Infect Dis 12:188
Mitchell, Caroline; Paul, Kathleen; Agnew, Kathy et al. (2011) Estimating volume of cervicovaginal secretions in cervicovaginal lavage fluid collected for measurement of genital HIV-1 RNA levels in women. J Clin Microbiol 49:735-6
Cattamanchi, Ashok; Saracino, Misty; Selke, Stacy et al. (2011) Treatment with valacyclovir, famciclovir, or antiretrovirals reduces human herpesvirus-8 replication in HIV-1 seropositive men. J Med Virol 83:1696-703

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