The non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been effective in durably suppressing HIV in combination with two nucleoside reverse transcriptase inhibitors (nRTIs) in both previously untreated HIV-infected patients and and nRTI-experienced patients as well or better than protease inhibitor-based regimens. One possible explanation for the effectiveness of combination therapy with the NNRTIs and nRTIs is that mutations conferring resistance to one class can increase the susceptibility of viruses to the other. Increasing numbers of nRTI mutations increases the susceptibility of isolates to NNRTIs. This NNRTI hypersusceptibility has been associated with improved short term virologic suppression in nucleoside-experienced subjects receiving NNRTI based therapies. Little is known about the mechanisms. An understanding of this newly described phenomenon is essential for both optimizing the use of these antiretrovirals in the clinical management of patients with HIV-1 infection, and for the development of new agents in the NNRTI class. Through analyses of patient-derived clones, site-directed mutants, and E. Coli expressed reverse transcriptases, the PI proposes to 1) determine if NNRTI hypersusceptibility is assay-independent, 2) determine its specific genetic correlates, and 3) determine the structural and biochemical mechanisms of NNRTI hypersusceptibility.
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