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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-AARR-D (40))
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Sakalian, Michael
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University of Minnesota Twin Cities
Schools of Medicine
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Nowarski, Roni; Prabhu, Ponnandy; Kenig, Edan et al. (2014) APOBEC3G inhibits HIV-1 RNA elongation by inactivating the viral trans-activation response element. J Mol Biol 426:2840-53
Li, Jinhui; Chen, Yan; Li, Ming et al. (2014) APOBEC3 multimerization correlates with HIV-1 packaging and restriction activity in living cells. J Mol Biol 426:1296-307
Macdonald, Patrick J; Johnson, Jolene; Chen, Yan et al. (2014) Brightness experiments. Methods Mol Biol 1076:699-718
Lyubchenko, Yuri L; Gall, Alexander A; Shlyakhtenko, Luda S (2014) Visualization of DNA and protein-DNA complexes with atomic force microscopy. Methods Mol Biol 1117:367-84
Lyubchenko, Yuri L (2014) Nanoscale Nucleosome Dynamics Assessed with Time-lapse AFM. Biophys Rev 6:181-190
Albin, John S; Brown, William L; Harris, Reuben S (2014) Catalytic activity of APOBEC3F is required for efficient restriction of Vif-deficient human immunodeficiency virus. Virology 450-451:49-54
Matsui, Yusuke; Shindo, Keisuke; Nagata, Kayoko et al. (2014) Defining HIV-1 Vif residues that interact with CBF? by site-directed mutagenesis. Virology 449:82-7
Shlyakhtenko, Luda S; Lushnikov, Alexander J; Li, Ming et al. (2014) Interaction of APOBEC3A with DNA assessed by atomic force microscopy. PLoS One 9:e99354
Matsui, Masashi; Shindo, Keisuke; Izumi, Taisuke et al. (2014) Small molecules that inhibit Vif-induced degradation of APOBEC3G. Virol J 11:122
Land, Allison M; Shaban, Nadine M; Evans, Leah et al. (2014) APOBEC3F determinants of HIV-1 Vif sensitivity. J Virol 88:12923-7

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