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Defining HIV-1 Vif residues that interact with CBFβ by site-directed mutagenesis

2013; Elsevier BV; Volume: 449; Linguagem: Inglês

10.1016/j.virol.2013.11.004

1096-0341

Yusuke Matsui, Keisuke Shindo, Kayoko Nagata, Katsuhiro Io, Kohei Tada, Fumie Iwai, Masayuki Kobayashi, Norimitsu Kadowaki, Reuben S. Harris, Akifumi Takaori‐Kondo,

Immune Cell Function and Interaction

Vif is essential for HIV-1 replication in T cells and macrophages. Vif recruits a host ubiquitin ligase complex to promote proteasomal degradation of the APOBEC3 restriction factors by poly-ubiquitination. The cellular transcription cofactor CBFβ is required for Vif function by stabilizing the Vif protein and promoting recruitment of a cellular Cullin5-RING ubiquitin ligase complex. Interaction between Vif and CBFβ is a promising therapeutic target, but little is known about the interfacial residues. We now demonstrate that Vif conserved residues E88/W89 are crucial for CBFβ binding. Substitution of E88/W89 to alanines impaired binding to CBFβ, degradation of APOBEC3, and virus infectivity in the presence of APOBEC3 in single-cycle infection. In spreading infection, NL4-3 with Vif E88A/W89A mutation replicated comparably to wild-type virus in permissive CEM-SS cells, but not in multiple APOBEC3 expressing non-permissive CEM cells. These results support a model in which HIV-1 Vif residues E88/W89 may participate in binding CBFβ.