Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HlV-1) is one of the most important challenges for chemotherapy of the early 21 st century. In the absence of an effective vaccine, a combination of inhibitors of HlV-1 reverse transcriptase and protease provide strong support for control of HIV infection. Recently, HlV-1 integrase inhibitors have also been added to this drug regimen. However, a major challenge in developing an effective therapy against HIV-1 is the emergence of multidrug-resistant virus strains, containing mutations in viral enzymes. Therefore, it is essential to obtain detailed mechanistic information on these key viral enzymes for the continued development of better drugs. During HlV-1 replication, the RNA genome is reverse transcribed into an integration competent double stranded DNA by HlV-1 reverse transcriptase. This viral DNA is subsequently integrated into the host genome by the HlV-1 integrase. My long term goal is to decipher the molecular details of interactions between essential viral and cellular enzymes with their nucleic acid substrates during retroviral replication. This is based on my preliminary and published data, where alterations in nucleic acid structure have influenced their recognition by HlV-1 reverse transchptase. The central hypothesis of the proposal is that structures of nucleic acids play an important role during retroviral replication. The rationale of my hypothesis is based on the manner in which retroviral enzymes accommodate conformationally-distinct nucleic acid substrates. Exploiting my nucleoside analog methodology and proposed virology training, I will validate my hypothesis with specific aims: 1) How does the nucleic acid structure/geometry influence HlV-1 integration and 2) How APOBEC3G recognizes the single stranded viral DNA. New and important biochemical data obtained from my studies will facilitate our understanding on the mechanism of HlV-1 replication, which is essential to design better and effective drugs against HIV.

Public Health Relevance

Gaining a deeper understanding of the interaction between HlV-1's nucleic substrates and its viral enzymes will reveal details about virus replication that will allow scientists to design more effective drugs against HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
5R00DA024558-05
Application #
8124967
Study Section
Special Emphasis Panel (NSS)
Program Officer
Pollock, Jonathan D
Project Start
2009-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$239,343
Indirect Cost
Name
Meharry Medical College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
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