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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI051199-01A1
Application #
6554329
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Bell, Dawn L
Project Start
2002-08-01
Project End
2007-04-30
Budget Start
2002-08-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$111,240
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Shulman, Nancy S; Kassaye, Seble G; Winters, Mark A et al. (2007) More on the treatment-tropism relationship: the impact of prior antiretroviral treatment on HIV coreceptor tropism among subjects entering AIDS clinical trials group 175. J Infect Dis 196:328-9;author reply 329-30
Campbell, Thomas B; Shulman, Nancy S; Johnson, Steven C et al. (2005) Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis 41:236-42
Shulman, Nancy S; Delgado, Jamael; Bosch, Ronald J et al. (2005) Nonnucleoside reverse transcriptase inhibitor phenotypic hypersusceptibility can be demonstrated in different assays. J Acquir Immune Defic Syndr 39:78-81
Shulman, Nancy S; Bosch, Ronald J; Mellors, John W et al. (2004) Genetic correlates of efavirenz hypersusceptibility. AIDS 18:1781-5