HIV/AIDS is a lifelong disease with global impact. Despite the development of effective therapies, there is an ongoing need to identify novel drug targets for improving the treatment of HIV infection. A poorly understood area of HIV biology is the stage in the virus infection process termed uncoating, which involves disassembly of the polymeric viral capsid from the viral core after entry into the cell. In collaboration with Pfizer Global Research and Development, we have begun to characterize the mechanism of novel small molecule HIV-1 inhibitors that target the viral capsid. Preliminary results indicate that these inhibitors block HIV-1 infection at an early stage by triggering premature uncoating of the virus in the target cell. This proposal includes a comprehensive plan involving the tools of structural biology, cell biology, and virology to define the molecular target and detailed mechanism of action of such capsid-targeting HIV-1 inhibitors.
The Specific Aims are: 1. To determine the structural consequences of PF-03450074 binding to the HIV-1 capsid. 2. To determine whether PF-03450074 promotes premature HIV-1 uncoating in target cells. 3. To determine the spectrum of mutations that confers resistance to PF-03450074. 4. To determine the mechanistic basis for the effects of the cyclophilin A-CA interaction on HIV-1 sensitivity to PF-03450074. 5. To determine the molecular basis of the late-stage inhibition by PF-03450074. The proposed research will identify a novel mechanism to inhibit HIV-1 infection, will reveal the structure of the target thereby facilitating the design of lead compounds for drug development, and will reveal new insights into the biology of HIV-1 infection.

Public Health Relevance

Effective treatment of HIV/AIDS requires the development of novel antiviral compounds that can complement the existing drug arsenal. This research project will define the mechanism of antiviral compounds acting on a novel HIV-1 target-the capsid. The studies proposed herein will facilitate the development of novel therapies and help elucidate the stage of HIV-1 infection termed uncoating.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089401-02
Application #
8021858
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Black, Paul L
Project Start
2010-02-15
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
2
Fiscal Year
2011
Total Cost
$728,256
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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