The discovery of the anti-viral APOBECS proteins is one of the most therapeufically promising breakthroughs in HIV/AIDS molecular virology in recent years. Humans have seven APOBECS proteins and at least two, APOBECSG and APOBECSF, are capable of inhibifing the replication of Vif-deficient HIV. However, HIV pathogenesis is due at least in part to the fact that the viral Vif protein counteracts these APOBECS proteins and triggers their degradation. The molecular approaches described in this proposal are an integral part of a larger program project to provide comprehensive knowledge of the structural, biophysical, biochemical and molecular features of these APOBECS proteins and their relation to HIV-1. First, we will test the hypothesis that APOBECSG dimerizafion occurs through multiple direct protein-protein interacfions, and we will determine the relevance of these interacfions to HIV restricfion. Second, we will disfinguish between two models for how APOBECSG binds single-strand DNA substrates analogous to HIV cDNA. Third, we will test the hypothesis that HIV Vif recognizes a common structural motif that is present in APOBECSF, APOBECSG, and other APOBECS proteins. We will use structural informafion from our program collaborafions to guide the construcfion of APOBECS and Vif mutants. These studies will be aided in part by a panel of novel APOBECSG inhibitory small molecules that will be used as molecular probes to dissect these crifical steps of the AP0BEC3G/F-mediated HIV-1 restriction mechanism. These studies will advance our fundamental understanding of APOBECSG and APOBECSF and facilitate the development of novel HIV/AIDS therapeufics that work by modulating the APOBECS-Vif pathway.
A therapeutically relevant host-pathogen conflict occurs between APOBECSF/APOBECSG and HIV-1 Vif. An intimate understanding of these APOBECS proteins and HIV-1 Vif is critical for ultimately designing and testing anti-retroviral drugs that work through this pathway.
|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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