We are characterizing structural determinants of HIV-1 Vif, HIV-2 Vif, A3G, and A3F that interact and induce degradation of A3G and A3F. The determinants of HIV-1 Vif that interact with A3G and A3F are not conserved in HIV-2 Vif, suggesting that HIV-2 Vif induces A3 protein degradation using distinct interactions. We are carrying out extensive mutational analysis of HIV-1 Vif, HIV-2 Vif, A3G, and A3F to identify structural determinants of each protein that interact with each other. We are also characterizing determinants of A3G-A3G interactions in cells using bimolecular fluorescence complementation. We are developing small-molecule inhibitors of A3G-Vif and A3F-Vif interactions. We have developed in situ assays for high-throughput screening of small-molecule inhibitors that interfere with HIV-1 Vif-mediated degradation of A3G and A3F. In collaboration with the NIH Chemical Genomics Center, we are screening a library of 300,000 compounds to identify inhibitors of this novel target for antiviral drug development. We are also identifying inhibitors of HIV-2 Vif and A3 interaction for the treatment of HIV-2 infection. We are determining the impact of A3G- and A3F-mediated hypermutation on the HIV-1 genome. To gain insight into the impact of hypermutation on viral evolution, we are carrying out ultradeep sequencing analysis to identify and characterize the entire HIV-1 genome with respect to A3-mediated G-to-A hypermutation target sites to identify mutational hotspots and coldspots. We are quantifying the antiviral activity of A3 proteins in primary CD4+ T cells and macrophages. We are determining the relative inhibitory potential of A3G and A3F in primary activated CD4+ T cells and macrophages using different modes of activation and cytokine stimulation to gain insights into their antiviral activity under various physiological conditions. We are analyzing the role of A3 proteins in P bodies, and the mechanism by which Mov10 inhibits retroviral replication. We have observed that Mov10 inhibits HIV-1 replication at the level of virus production and reverse transcription. To elucidate the mechanism of inhibition, we are analyzing Mov10 virion incorporation and its effects on Gag expression and reverse transcription. To gain insights into the interactions of APOBEC3 proteins with viral components after infection, we are using live-cell imaging to determine the kinetics with which APOBEC3 proteins dissociate from the viral preintegration complexes. [Corresponds to Pathak Project 2 in the October 2011 site visit report of the HIV Drug Resistance Program]

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Chaipan, Chawaree; Smith, Jessica L; Hu, Wei-Shau et al. (2013) APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4+ T cells and macrophages. J Virol 87:444-53
Izumi, Taisuke; Burdick, Ryan; Shigemi, Mayu et al. (2013) Mov10 and APOBEC3G localization to processing bodies is not required for virion incorporation and antiviral activity. J Virol 87:11047-62
Paprotka, Tobias; Venkatachari, Narasimhan J; Chaipan, Chawaree et al. (2010) Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J Virol 84:5719-29
Jern, Patric; Russell, Rebecca A; Pathak, Vinay K et al. (2009) Likely role of APOBEC3G-mediated G-to-A mutations in HIV-1 evolution and drug resistance. PLoS Pathog 5:e1000367
Friew, Yeshitila N; Boyko, Vitaly; Hu, Wei-Shau et al. (2009) Intracellular interactions between APOBEC3G, RNA, and HIV-1 Gag: APOBEC3G multimerization is dependent on its association with RNA. Retrovirology 6:56
LaRue, Rebecca S; Andresdottir, Valgerdur; Blanchard, Yannick et al. (2009) Guidelines for naming nonprimate APOBEC3 genes and proteins. J Virol 83:494-7
Perkovic, Mario; Schmidt, Stanislaw; Marino, Daniela et al. (2009) Species-specific inhibition of APOBEC3C by the prototype foamy virus protein bet. J Biol Chem 284:5819-26
Russell, Rebecca A; Smith, Jessica; Barr, Rebekah et al. (2009) Distinct domains within APOBEC3G and APOBEC3F interact with separate regions of human immunodeficiency virus type 1 Vif. J Virol 83:1992-2003
Russell, Rebecca A; Moore, Michael D; Hu, Wei-Shau et al. (2009) APOBEC3G induces a hypermutation gradient: purifying selection at multiple steps during HIV-1 replication results in levels of G-to-A mutations that are high in DNA, intermediate in cellular viral RNA, and low in virion RNA. Retrovirology 6:16
Chen, Jianbo; Pathak, Vinay K; Peng, Weiqun et al. (2008) Capsid proteins from human immunodeficiency virus type 1 and simian immunodeficiency virus SIVmac can coassemble into mature cores of infectious viruses. J Virol 82:8253-61