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.
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