Hypothesis: HIV-RNA shedding will occur intermittently from the female genital mucosa, similar to viral RNA """"""""blips"""""""" in the plasma. Evolution of drug resistance mutations will be detectable in the viral nucleic acids of women who subsequently loose suppression of viral replication with their plasma HIV-1 RNA increasing to > 200 copies/ml. Whereas, the genital and plasma RNA detected in """"""""blips"""""""" among women who continue to exhibit suppression of replication, ( and maintain HIV-1 RNA levels generally < 50 copies/ml) will be """"""""wild type"""""""".
Aims : 1. Characterize the frequency, quantity and genotype of HIV-1 RNA shedding from the genital tract of women during effective HAART (plasma HIV-1 RNA generally < 50 copies/ml). Compare the quantity of HIV-1 RNA, 2LTR DNA and pol and env genotypes in the genital tract virus to the plasma and PBMC virus. 2. Among women with plasma generally <50 copies/ml, characterize the pol and env genomes in the genital RNA shed and in pro-virus from cytobrush and biopsies of the uterine cervic in terms of mutations associated with drug resistance and population diversity and interchange with the blood virus. 3. Among women with plasma generally <50 copies/ml, characterize the pol and env genomes in terms of whether HIV-1 anti-retrovirals differs by the cell type. Rationale: HIV-1 RNA shedding will occur intermittently from the female genital mucosa, similar to """"""""blips"""""""" in the plasma. Amongst women infected but penile-vaginal intercourse, the greatest reservoir of HIV-1 genetic diversity will likely be in the genital tract and this virus is a likely source for evolution of resistant virus. Increased genetic diversity of vaginal virus would have originated would have originated from exposure to a genetically diverse quasispecies in semen at the time of infection. A greater genetic diversity of vaginal virus would increase the likelihood of selection of viral variants with resistance genotypes at this site. HIV-1 mutations associated with resistance to anti-retrovirals could be detectable first in the vagina, with these viruses then disseminating to the plasma, lymphoid and other tissues. Local inflammation due to infections could also enhance the conditions for viral replication in the genital tract and increase the likelihood of HIV-1 replication in the genital tract and increase the likelihood of HIV-1 replication and the chance of evolution of resistant virus. In addition, practical methods will be evaluated, including a 2LTR and measurements of an increase in genomic diversity, for their utility in the timely prediction of that resistance is emerging.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
3P01HD040540-02S1
Application #
6660127
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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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