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T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction

Abstract

The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1)1,2,3,4,5,6. HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C 7,8,9, which promotes the polyubiquitination and degradation of APOBEC3 substrates7,10,11,12,13,14. Here we demonstrate in human T cells that core binding factor β (CBF-β) is a key regulator of the evasion of HIV-1 from the host defence mediated by APOBEC3. CBF-β, the non-DNA-binding subunit of a heterodimeric transcription factor, regulates the folding and DNA-binding activity of partner RUNX family proteins, which have important roles in the development and differentiation of diverse cell types, including T lymphocytes15,16. In our study, knockdown of endogenous CBF-β blocked Vif-induced APOBEC3G polyubiquitination and degradation. CBF-β was not required for the interaction between Vif and APOBEC3G, yet was essential for the assembly of the Vif–CUL5 E3-ubiquitin-ligase complex. CBF-β proved to be a unique regulator of primate lentiviral Vif and not a general component of the CUL5 E3 ubiquitin ligase. We show that Vif and CBF-β physically interact, and that the amino-terminal region of Vif is required for this interaction. Furthermore, interactions with Vif required regions in CBF-β that are not involved in RUNX protein binding17,18,19. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.

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Figure 1: Characterization of the functional interaction between HIV-1 Vif and CBF-β.
Figure 2: CBF-β is critical for the interaction between Vif and CUL5.
Figure 3: Identification of regions in CBF-β is important for HIV-1 Vif interaction.
Figure 4: Vif-induced polyubiquitination of APOBEC3G requires CBF-β.

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Acknowledgements

We thank K. Strebel, A. Friedman, N. Speck, D. Yue, R. Siliciano, M. Malim, R. Harris, T. Inoue and D. Gabuzda for critical reagents; T. Wang, K. Zhao, X. Zhou and A. Zhen for technical assistance; R. Markham, J. Margolick and J. Bream for thoughtful discussions; and D. McClellan for editorial assistance. We also wish to thank staff within the Mass Spectrometry Core and the Institute for Basic Biomedical Sciences Microscope Facility at Johns Hopkins School of Medicine for their technical assistance. The following reagents were obtained through the AIDS Research and Reference Reagents Program, Division of AIDS, NIAID, NIH: monoclonal antibodies against HIV-1 p24 (B. Chesebro and H. Chen), pNL4-3 (M. Martin), pcDNA-hVif (S. Bour and K. Strebel), antiserum to HIV-1 Vif (D. Gabuzda) and MAGI-CCR5 cells (J. Overbaugh). This work was supported in part by funding from the Chinese Ministry of Science and Technology (2012CB911100) and Chinese Ministry of Education (IRT1016), the Key Laboratory of Molecular Virology, Jilin Province (20102209), China, and a grant (2R56AI62644-6) from the NIAID.

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W.Z., J.D., S.L.E. and Y.Y. performed experiments and analysed the data. X.-F.Y. directed the project, analysed the data, and wrote the paper with help from all authors.

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Correspondence to Xiao-Fang Yu.

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Zhang, W., Du, J., Evans, S. et al. T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction. Nature 481, 376–379 (2012). https://doi.org/10.1038/nature10718

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