宿主Den1蛋白负调控HIV/SIV Vpx蛋白功能的作用机制研究

Acquired Immune Deficiency Syndrome（AIDS）, as a global infectious disease, is major caused by infection of human immunodeficiency virus (HIV). HIV-2 and closely related SIV Vpx protein hijacks CRL4 ubiquitin ligase to induce host restriction factor SAMHD1 degradation, and promote virus infection in macrophages. Recently, we have identified that Neddylation is required for the functions of viral protein Vpx. However, roles of host deneddylases on Vpx activities are poorly investigated. Our preliminary experiments have demonstrated that deneddylase Den1 potently suppressed Vpx-mediated SAMHD1 degradation. In this project, we will focus to investigate the interaction between Den1 and Vpx-CRL4 ligase, analyze the mechanisms of Vpx inhibition by Den1, define the broad spectrum of suppression for diverse HIV-2/SIV Vpx activities and viral infection. Furthermore, we will expound viral evasion of HIV/SIV to the inhibition of Den1. Our studies would deeply elucidate effects of cellular Neddylation and Deneddylation on virus infection, and should be helpful for novel antiviral drug development.

艾滋病作为全球重大危害性传染病，其主要致病因是HIV病毒。其中，HIV-2病毒及同源病毒SIV编码的辅助蛋白Vpx依赖CRL4泛素连接酶诱导宿主抗病毒因子SAMHD1降解，促进病毒侵染巨噬细胞。申请人及所在团队已率先证实类泛素化修饰Neddylation对病毒蛋白Vpx功能至关重要，但是，宿主去类泛素化酶对Vpx功能的调控作用罕有报道。本项目预实验结果发现去类泛素化酶Den1具有显著抑制Vpx蛋白介导SAMHD1降解的能力，拟围绕Den1与Vpx-CRL4复合体的相互作用，阐明Den1抑制Vpx功能的作用机制；明确Den1蛋白抑制Vpx蛋白功能及HIV/SIV病毒侵染的广谱性；并进一步探讨HIV/SIV病毒对Den1蛋白抑制活性的逃逸机制。本项目将深入阐释细胞内Neddylation的修饰与去修饰调控对艾滋病病毒感染的影响，为设计以Neddylation为靶标的新型抗病毒药物提供重要参考。

本项目研究证实去类泛素化酶Den1具有显著抑制Vpx蛋白介导SAMHD1降解的能力，围绕Den1与Vpx-CRL4复合体的相互作用，阐明了Den1抑制Vpx功能的作用机制；明确了Den1蛋白抑制Vpx蛋白功能及HIV/SIV病毒侵染的广谱性；检测了HIV/SIV病毒对Den1蛋白抑制活性的逃逸机制。本项目还进一步阐释了细胞内Neddylation的修饰与去修饰调控对多种不同病毒蛋白功能与病毒感染的影响，为设计以Neddylation为靶标的新型抗病毒药物提供了重要参考。