The APOBEC3 (A3)-Vif interaction dictates whether HIV 'lives'or 'dies'. In a normal infection, HIV uses its auxiliary protein Vif to neutralize the cellular retroviral restriction factors A3G and A3F. Conversely, in the absence of Vif, these A3 proteins are able to potently inhibit HIV infectivity. The A3-Vif interaction has therefore become a prime target for the development of novel therapeutic interventions. However, a current impediment to therapeutic development is a vast knowledge gap owing to the fact that there are precious few structural, biophysical and biochemical studies on these A3 proteins or HIV Vif. To fill this gap, we have assembled a truly multidisciplinary Program Project that combines the strengths of five laboratories, each with complementary sets of expertise in molecular virology, NMR spectroscopy, X-ray crystallography, AFM force spectroscopy and biochemistry. Our projects are assembled to achieve the following broad, high-impact objectives: (i) elucidate the full-length A3G structure and gain a comprehensive understanding for how this protein oligomerizes during HIV restriction, (ii) define how A3G binds single-strand DNA and catalyzes cytidine to uridine deamination, and (iii) dissect the Vif interaction surfaces of A3G and A3F to fully understand critical similarities and differences. We will also use novel A3G inhibitors and small peptides as molecular probes to dissect stages of the DNA deamination mechanism. Each investigator will apply his/her specific expertise to each of these aims and our team will work toward building-up the 'big picture'for how A3F and A3G mediate HIV-1 restriction and how Vif counteracts these multifaceted and potent innate immune defenses. Overall, this Program Project will provide unprecedented atomic, biophysical, biochemical, and molecular information. We anticipate that this knowledge will help accelerate the development and implementation of novel HIV/AIDS therapeutics that work by leveraging the A3/Vif axis.

Public Health Relevance

A life-or-death host-pathogen conflict occurs between the human AP0BEC3 proteins and HIV Vif. Understanding the atomic, biochemical, biophysical and molecular details of the interactions that occur between these proteins will be essential for ultimately designing and testing novel HIV/AIDS therapies that work by leveraging this important pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM091743-02
Application #
8233319
Study Section
Special Emphasis Panel (ZRG1-AARR-D (40))
Program Officer
Sakalian, Michael
Project Start
2011-03-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$1,932,999
Indirect Cost
$402,878
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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