Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin, 130061, China.
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
Biochem Biophys Res Commun. 2019 Apr 16;511(4):910-915. doi: 10.1016/j.bbrc.2019.02.136. Epub 2019 Mar 7.
Interaction between HIV-1 Vif and host factor CBFβ leads to the assembly of the Vif-Cul5-EloB/C ubiquitin ligase (E3 complex). By inducing the formation of E3 complex, Vif depletes host APOBEC3 restriction factors and promotes HIV-1 infection. In addition, Vif is known to arrest host cells at G2/M phase (G2 arrest), benefiting HIV-1 replication and contributing to the depletion of CD4 T cells. However, whether CBFβ is also involved in Vif-induced cell cycle arrest remains unclear. In the present study, we report that CBFβ is an essential factor for Vif-induced G2 arrest. Reducing endogenous CBFβ expression significantly compromised Vif's potency in cell cycle regulation. In addition, tests with CBFβ and Vif mutants indicated that Vif-CBFβ interaction is crucial for Vif to induce G2 arrest. Furthermore, suppressors against Vif-hijacked E3 complex or proteasome-mediated proteolysis also abolished Vif's ability to cause G2 arrest. In general, our data indicated that Vif induces G2 arrest through depletion of a yet-unknown cellular factor, where the involvement of CBFβ is essential. On the other hand, our data also suggested that, antiviral drugs targeting the Vif-CBFβ interaction have the potential to abolish Vif's ability to cause APOBEC3 degradation as well as G2 arrest in host cells, thus reducing both HIV-1 replication and Vif-induced CD4 T-cell depletion.
HIV-1 Vif 与宿主因子 CBFβ 的相互作用导致 Vif-Cul5-EloB/C 泛素连接酶 (E3 复合物) 的组装。通过诱导 E3 复合物的形成，Vif 耗尽宿主 APOBEC3 限制因子并促进 HIV-1 感染。此外，Vif 已知会使宿主细胞停滞在 G2/M 期（G2 期停滞），有利于 HIV-1 复制并导致 CD4 T 细胞耗竭。然而，CBFβ 是否也参与 Vif 诱导的细胞周期停滞仍不清楚。在本研究中，我们报告 CBFβ 是 Vif 诱导的 G2 期停滞所必需的因素。降低内源性 CBFβ 表达显著削弱了 Vif 在细胞周期调控中的效力。此外，用 CBFβ 和 Vif 突变体进行的测试表明，Vif-CBFβ 相互作用对于 Vif 诱导 G2 期停滞至关重要。此外，针对 Vif 劫持的 E3 复合物或蛋白酶体介导的蛋白水解的抑制剂也消除了 Vif 引起 G2 期停滞的能力。总的来说，我们的数据表明，Vif 通过耗尽一个未知的细胞因子来诱导 G2 期停滞，其中 CBFβ 的参与是必不可少的。另一方面，我们的数据还表明，针对 Vif-CBFβ 相互作用的抗病毒药物有可能消除 Vif 降解 APOBEC3 以及在宿主细胞中引起 G2 期停滞的能力，从而降低 HIV-1 复制和 Vif 诱导的 CD4 T 细胞耗竭。
