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

The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1). HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C , which promotes the polyubiquitination and degradation of APOBEC3 substrates. 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 lymphocytes. 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 binding. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.

Pubmed ID: 22190036

Authors

  • Zhang W
  • Du J
  • Evans SL
  • Yu Y
  • Yu XF

Journal

Nature

Publication Data

January 19, 2012

Associated Grants

  • Agency: NIAID NIH HHS, Id: 2R56AI62644-6
  • Agency: NIAID NIH HHS, Id: F31 AI091326-01A1
  • Agency: NIAID NIH HHS, Id: F31 AI091326-02

Mesh Terms

  • Cell Differentiation
  • Cell Line
  • Core Binding Factor alpha Subunits
  • Core Binding Factor beta Subunit
  • Cullin Proteins
  • Cytidine Deaminase
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HIV-1
  • Host-Pathogen Interactions
  • Humans
  • Immune Evasion
  • Immunoprecipitation
  • Models, Molecular
  • Protein Binding
  • Proteolysis
  • T-Lymphocytes
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • vif Gene Products, Human Immunodeficiency Virus