Nucleoside analog reverse transcriptase inhibitors (NRTIs) were the first therapeutic agents to demonstrate clinical efficacy for HIV-1 infection, and continue to be the cornerstone of highly active antiretroviral therapy (HAART) for HIV-1. Host factors play important roles in susceptibility to antiviral agents such as NRTIs;deoxynucleoside triphosphate (dNTP) pool size and DNA exonuclease, TREX-1, are of particular interest based on our preliminary results. Our laboratory recently discovered a new NRTI, 4'-ethynylstavudine (4'-Ed4T). 4'- Ed4T has much better therapeutic index in cell culture than either zidovudine (AZT) or stavudine (D4T). The active metabolites of 4'-Ed4T have longer intracellular half lives and we have had difficulty in generating highly resistant HIV virus to 4'-Ed4T in culture. We hypothesize that 4'-Ed4T may present a higher genetic barrier to the development of highly drug resistance mutations. It is currently under Phase Ib/2a clinical trial and has demonstrated impressive anti-HIV effect. The main objectives of this application are to study two host factors that may affect the efficacy of NRTIs and to characterize resistance to 4'-Ed4T. We propose the three specific aims: 1. Determine the role of intracellular dNTP content on the anti-HIV activity of selected NRTIs. 2. Explore the role of cytoplasmic Exo, TREX-1, in HIV antiviral activity of NRTI and HIV replication. 3. Explore the evolution of 4'-Ed4T resistant HIV and characterization of the resistant virus.
The Specific Aim 1 will develop a more reliable, sensitive, and time saving method to address the role of endogenous dNTP in determining NRTI activity.
Specific Aim 2 will also explore the potential role of TREX-1 in NRTI antiviral activity and HIV replication. Future HAART protocols could take into consideration the difference in TREX-1 expression in target cells of individuals to avoid individual variation in response to some NRTIs. The studies proposed will provide information on why it is difficult to develop resistance to 4'-Ed4T and the behaviors of the highly resistant virus to 4'-Ed4T. This will help in the clinical development of 4'-Ed4T;either as a single drug or as part of a simplified HAART.

Public Health Relevance

Host Factors affecting antiviral activity of HIV nucleoside analogs, HIV replication and novel mechanism of resistant to a new anti-HIV compound, 4'-Ed4T.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038204-18
Application #
8286296
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Turk, Steven R
Project Start
1995-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$409,613
Indirect Cost
$162,113
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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