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T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction
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T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction
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Journal Article
T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction
2012
Overview
CBF-β is shown to regulate the ability of HIV-1 to evade host restriction mediated by the deaminase APOBEC3.
Vif–CBF-β interaction an anti-HIV-1 target
The transcription cofactor CBF-β (core binding factor β) regulates the DNA binding activity of RUNX family proteins. Two independent studies now show that CBF-β also regulates the ability of HIV-1 to evade host restriction mediated by the cDNA deaminase APOBEC3G, a host factor that blocks viral replication. They show that it associates with the HIV protein Vif, and is essential for the assembly of the Vif-Cul5 E3 ubiquitin ligase complex, which mediates the ubiquitination and destruction of APOBEC3. Both groups suggest that disrupting the Vif–CBF-β interaction could provide a new therapeutic target against HIV-1 infection.
The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1)
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. HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C
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, which promotes the polyubiquitination and degradation of APOBEC3 substrates
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. 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
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. 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
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. Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biological and medical sciences
/ Core Binding Factor alpha Subunits - metabolism
/ Core Binding Factor beta Subunit - chemistry
/ Core Binding Factor beta Subunit - deficiency
/ Core Binding Factor beta Subunit - genetics
/ Core Binding Factor beta Subunit - metabolism
/ Cullin Proteins - metabolism
/ Cytidine Deaminase - genetics
/ Cytidine Deaminase - metabolism
/ Fundamental and applied biological sciences. Psychology
/ Human immunodeficiency virus 1
/ Humanities and Social Sciences
/ Humans
/ letter
/ Primates
/ Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains
/ Science
/ T cells
/ Ubiquitin-Protein Ligases - metabolism
/ vif Gene Products, Human Immunodeficiency Virus - chemistry
/ vif Gene Products, Human Immunodeficiency Virus - genetics
/ vif Gene Products, Human Immunodeficiency Virus - metabolism
/ Virology
