The Biochemical Mechanisms Of Host Protein CBF-B Regulating Primate Lentiviral Vif Function

Lentivirus causes long term and progressive human and animals acquired immunodeficiency syndrome (AIDS). Common lentiviruses include human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), caprine arthritis encephalitis virus (CAEV), maedi-visna virus (MVV), and the only viral infectivity factor (Vif)-deficient virus, equine infectious anemia virus (EIAV). Although the donkey leukocyte attenuated vaccine of EIAV has a broad-spectrum and high efficiency protection to EIAV infection, and inactivated vaccine of FIV has partially protection to some FIV strains, there are no available vaccines to other lentiviruses. Therefore, the antiviral therapy for lentiviruses, especially for AIDS caused by HIV-1, became the major method for treating lentiviruses. Currently, most drugs target the enzymes of the virus to block the replication of the viral life cycle to cure AIDS, however, the evolution and mutation of the viral genome has created drug resistance in the virus, indicating it is urgent to discover new antiviral targets.The innate immunity restriction factor, APOBEC3-family proteins were expressed in several HIV-1 target cells. APOBEC3 caused lethal mutations in the viral genome to inhibit the replication of HIV-1. HIV-1 Vif protein induced the degradation of APOBEC3 to clean the determent environment in the host cells. Recent researches have indicated that host protein CBF-β was required for HIV-1 Vif to induce APOBEC3 degradation. Silencing the expression of CBF-β descressed the degradation of APOBEC3 by HIV-1 Vif, then APOBEC3 block the replication of HIV-1. Therefore, the interruption of interaction between CBF-β and HIV-1 Vif have become the new antiviral target. The understanding of the biochemical mechanisms by which CBF-3 function to HIV-1 Vif was beneficial to the design and synthesis of antiviral drugs.We analyzed common lentiviral Vif proteins and found that CBF-β was required for primate lentiviral Vif function but not that of non-primate lentiviral Vif. Using non-primate lentiviral Vifs as a control, we found CBF-β changed several biochemical features of primate lentiviral Vifs, including increasing their stability and half-life, decreasing their oligomerization and changed their cellular distribution. Moreover, through the comparison with CBF-β or Vif mutants, we concluded that the alteration of Vif conformation and the extending of protein stability was the main reason for CBF-β mediated Vif functioning. Therefore, we explored the mechanisms by which CBF-β promoted Vif stability. We found the binding of CBF-β to Vif decreased the ubiquitin modification of several lysines in HIV-1 Vif. Then the degradation of HIV-1 Vif descreased and the stability of HIV-1 Vif increased.