A3G, A3F, and Mov10 localize to cytoplasmic puncta known as P bodies and inhibit HIV-1 replication. We explored the functional significance of P-body localization for Mov10 and A3 proteins and found that P-body localization is not required for their virion incorporation or antiviral activity. We performed a genome-wide siRNA screen to identify host proteins that facilitate HIV-1 Vif (Vif1)-mediated degradation of A3 proteins. One factor that the screen identified is UBA52, a ubiquitin-ribosomal protein L40 fusion protein; we are characterizing the role of UBA52 in Vif-mediated degradation of A3 proteins. In addition to UBA52, our genome-wide siRNA screen identified other host factors that potentially facilitate Vif1-induced degradation of A3G, including UBE4B, UBE3A, KAT5, and WDR82. We will examine the role of these and other candidate hits to determine how these factors facilitate degradation of A3 proteins in the presence of Vif1. There is little homology between Vif1 and Vif2 proteins, and our recent studies indicate that Vif1 and Vif2 interact with A3 proteins by using completely different determinants. Our current studies suggest that there are significant differences in the mechanisms by which Vif1 and Vif2 induce degradation of A3 proteins. We will elucidate the mechanism of Vif2-mediated degradation of A3 proteins. CBF-beta is a host factor that binds to Vif1 and increases its stability and antiviral activity. We observed that Vif2 does not interact with CBF-beta. We will carry out coimmunoprecipitation and mass spectrometry studies to identify Vif2-interacting proteins and determine whether another host factor serves the same function as CBF-beta. HIV-1 groups N, O, and P have infected humans by zoonotic transmission of simian immunodeficiency viruses. We are characterizing the interactions between these HIV-1 Vif proteins and human A3G and A3F proteins and comparing their interactions with those of group M Vif. Although A3G, A3F, and A3D are expressed in human CD4+ T cells, their relative contribution to restriction of Vif-defective HIV-1 is unknown. We used HIV-1 Vif mutants that were defective in their ability to degrade either A3G or A3F/A3D and found that A3G more potently restricts HIV-1 than do A3F and A3D. It is not known whether A3G and A3F can copackage into the same virions and comutate the same HIV-1 genomes. We are determining the potential of A3G and A3F to copackage into the same virions and comutate HIV-1 genomes. It is not known whether mutations induced by A3G and A3F contribute to viral genetic variation and/or influence the frequency of retroviral recombination. We are carrying out experiments to determine whether G-to-A mutations induced by A3G and A3F contribute to viral genetic diversification and evolution. _____[Corresponds to Pathak Project 2 in the October 2011 site visit report of the HIV Drug Resistance Program]
| Maiti, Atanu; Myint, Wazo; Kanai, Tapan et al. (2018) Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA. Nat Commun 9:2460 |
| Desimmie, Belete A; Smith, Jessica L; Matsuo, Hiroshi et al. (2017) Identification of a tripartite interaction between the N-terminus of HIV-1 Vif and CBF? that is critical for Vif function. Retrovirology 14:19 |
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| Delviks-Frankenberry, Krista A; Nikolaitchik, Olga A; Burdick, Ryan C et al. (2016) Minimal Contribution of APOBEC3-Induced G-to-A Hypermutation to HIV-1 Recombination and Genetic Variation. PLoS Pathog 12:e1005646 |
| Chikaev, Anton N; Bakulina, Anastasiya Yu; Burdick, Ryan C et al. (2015) Selection of peptide mimics of HIV-1 epitope recognized by neutralizing antibody VRC01. PLoS One 10:e0120847 |
| Sardo, Luca; Hatch, Steven C; Chen, Jianbo et al. (2015) Dynamics of HIV-1 RNA Near the Plasma Membrane during Virus Assembly. J Virol 89:10832-40 |
| Sato, Kei; Takeuchi, Junko S; Misawa, Naoko et al. (2014) APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model. PLoS Pathog 10:e1004453 |
| Smith, Jessica L; Izumi, Taisuke; Borbet, Timothy C et al. (2014) HIV-1 and HIV-2 Vif interact with human APOBEC3 proteins using completely different determinants. J Virol 88:9893-908 |
| Desimmie, Belete A; Delviks-Frankenberrry, Krista A; Burdick, Ryan C et al. (2014) Multiple APOBEC3 restriction factors for HIV-1 and one Vif to rule them all. J Mol Biol 426:1220-45 |
| Burdick, Ryan C; Hu, Wei-Shau; Pathak, Vinay K (2013) Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes. Proc Natl Acad Sci U S A 110:E4780-9 |
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