Viral resistance is a serious consequence of incomplete suppression of HIV-1 replication. Viral resistance eventually affects from 30% to 50% of all patients undergoing highly active anti-retroviral therapy (HAART). Once HAART resistance is present regaining control of plasma viremia becomes difficult because no clearly effective salvage strategy has been devised. Often, the final result of HAART failure is that a preexistent or generated set of mutations that confer resistance is positively selected. Clearly, this selection is directly applied at the pol gene, reverse transcriptase (RT) and protease coding regions, but the selected pol gene should be linked with the rest of the viral genome, including the highly immunogenic envelope gene. We therefore, expect this genomic linkage to have a genomic restriction effect at the envelope gene. The applicants hypothesize that HAART therapy while effective (viral loads of less than 400 copies/ml, of plasma) will restrict viral genetic variability so that eventual HAART failure, (more than 400 copies/ml of plasma) will result in the initial emergence of a plasma virus population that is more homogeneous genetically than the viral population prior to initiation of therapy. The existence of this """"""""window of homogeneity"""""""" and the duration of this window, especially if it is also reflected at the envelope gene, may offer opportunities for therapeutic intervention that may be less effective when the virus is genetically more heterogeneous. Therefore, the applicants propose to sub-clone, sequence and analyze the C2-V3 region of the envelope gene, before HAART initiation and after HAART failure, from the plasma virus of a well-defined cohort of patients. They will also sub-clone, sequence and analyze the appropriate regions of the pol gene, RT and protease. The applicants will conduct these studies with the purpose of characterizing and documenting the development of selection at the pol gene that emerges from HAART failure, and whether it consequently reflects as a restriction of variability at the envelope gene. The applicant also expect to document any prevalent pattern of tropism restriction at the envelope gene. To accomplish these two goals, they will phylogenetically compare HAART failure quasi-species with the quasi-species before HAART and both these groups of quasi-species with the V-3 consensus motif that predicts CCR5 (M-tropic) co-receptor usage. This propose study will focus on genetic evolution and antigenic restriction of HIV in circulating blood of patients undergoing HAART. The applicants believe it is critical to know if this homogeneous (less heterogeneous) window period exists, in which the highly immunogenic envelope gene protein will be a more stable and/or predictable target for future therapeutic approaches.
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