CBFβ Stabilizes HIV Vif to Counteract APOBEC3 at the Expense of RUNX1 Target Gene Expression

The HIV-1 accessory protein Vif hijacks a cellular Cullin-RING ubiquitin ligase, CRL5, to promote degradation of the APOBEC3 (A3) family of restriction factors. Recently, the cellular transcription cofactor CBF beta was shown to form a complex with CRL5-Vif and to be essential for A3 degradation and viral infectivity. We now demonstrate that CBF beta is required for assembling a well-ordered CRL5-Vif complex by inhibiting Vif oligomerization and by activating CRL5-Vif via direct interaction. The CRL5-Vif-CBF beta holoenzyme forms a well-defined heterohexamer, indicating that Vif simultaneously hijacks CRL5 and CBF beta. Heterodimers of CBF beta and RUNX transcription factors contribute toward the regulation of genes, including those with immune system functions. We show that binding of Vif to CB93 is mutually exclusive with RUNX hetero-dimerization and impacts the expression of genes whose regulatory domains are associated with RUNX1. Our results provide a mechanism by which a pathogen with limited coding capacity uses one factor to hijack multiple host pathways.