DLV (Delavirdine) is a highly active, nonnucleoside reverse transcriptase inhibitor(NNRTI) which has been approved for clinical use in HIV infection. In tissue culture experiments, the predominant HIV variant that is selected for encodes a p236L mutation in reverse transcriptase (RT). However, in clinical trials, the P236L mutations is infrequent in clinical isolates, rather Y181C and K103N mutations are more common. This indicates that factors other than those present under tissue culture conditions favor the outgrowth of resistant species. In preliminary studies to explore these factors, the investigators have shown that recombinant virus encoding the P236L mutant has a replication disadvantage, and that recombinant RT with P236L mutant has a replication disadvantage, and that recombinant RT with P236L shows decreased processivity and an increase in pausing. The major goal of this proposal is to further understand the mechanisms for decreased replication fitness of the P236L mutant.
The specific aims of the proposal are to: 1) determine the biochemical mechanisms responsible for the defect of the P236L RT, 2) study the replication of kinetics of P236L containing viruses as well as wild-type and other NNRTI mutants, 3) determine the impact of other RT inhibitors on the relative replication fitness of P236L and other mutants, and 4) determine whether there are RT polymorphisms that can compensate for the reduced fitness of P236L.
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