The Evolution of Vpr/Vpx Function in Primate Lentiviruses

灵长类慢病毒Vpr/Vpx功能的进化

• 批准号: 8602705
• 负责人: Michael Emerman
• 金额: $ 32.52万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602705
• 关键词: Address; Affect; Antiviral Agents; Biology; Cell Cycle; Cells; Cercopithecus pygerythrus; Data; Dendritic Cells; Evolution; G2 Phase; Genes; Genetic Polymorphism; Genome; Grant; HIV; HIV therapy; HIV-1; HIV-2; Host Defense; Human; Individual; Infection; Intervention; Modeling; Molecular; Nature; Nucleotides; Pharmaceutical Preparations; Population; Primate Lentiviruses; Primates; Proteins; Race; Relative (related person); Rest; Source; Specificity; Subfamily lentivirinae; T-Lymphocyte; Testing; Viral; Viral Genes; Virus; Virus Replication; arm; base; in vivo; macrophage; monocyte; novel; pandemic disease; pathogen; protein degradation; public health relevance; research study; tool; transmission process; virus host interaction; vpr Gene Products; vpr Genes

DESCRIPTION (provided by applicant): HIV-1 and other primate lentiviruses encode accessory genes that serve to enhance virus replication and counteract host antiviral factors. These restriction factors have the capacity to limit virus replication and influence cross-species transmissions of lentiviruses. Moreover, the interactions between viral accessory proteins and host restriction factors are a potential source of novel drug interventions for HIV therapy. Vpx and Vpr are two related lentiviral accessory proteins. While all primate lentiviruses encode Vpr, only two of them encode Vpx as well. Vpx is critical for the ability of primate lentiviruses to efficiently infect monocytes, dendritic cells, macrophages, and resting T cells, while Vpr has many ascribed functions including the ability to arrest cells in the G2 phase of the cell cycle. Recently, the target of Vpx has been identified as the host restriction factor SAMHD1 which is targeted for degradation by Vpx. An evolutionary analysis to understand the functional relationship of Vpx and Vpr showed that Vpx and Vpr have overlapping functions. Vpx proteins from diverse lentiviruses as well as Vpr proteins from some lentiviruses both have the ability to target their host species' SAMHD1 for degradation. However, HIV-1 Vpr does not interact with SAMHD1, and therefore the importance of this virus-host interaction remains a mystery. In this grant we will determine the importance of the SAMHD1 interaction by examining the host-virus evolution in a natural infection study of African green monkeys and their lentirviral infections. Furthermore, we will determine how Vpx/Vpr and SAMHD1 have co-evolved to recognize and escape each another by determining the molecular basis by which SAMHD1 proteins from different primate hosts are recognized by different Vpx/Vpr proteins. We will also examine the interactions of Vpx from a human pathogen, HIV-2 with human SAMHD1 and will explore the possibility that some HIV-1 strains also encode a Vpr protein that is capable of degrading SAMHD1. Finally, we will test the hypothesis that new functions for Vpr and Vpx have evolved on top off pre-existing functions by determining the ancestral function of Vpr and by determining how some Vpr proteins can have multiple functions.

描述（由申请人提供）：HIV-1和其他灵长类动病毒编码可增强病毒复制和抵消宿主抗病毒因子的附属基因。这些限制因素具有限制病毒复制的能力并影响慢病毒的跨物种传播。此外，病毒辅助蛋白与宿主限制因素之间的相互作用是HIV治疗的新型药物干预措施的潜在来源。 VPX和VPR是两个相关的慢病毒附件蛋白。虽然所有灵长类动物慢病毒编码VPR，但也只有两个编码VPX。 VPX对于灵长类动物慢病毒有效感染单核细胞，树突状细胞，巨噬细胞和静息T细胞的能力至关重要，而VPR具有许多归因的功能，包括在细胞周期的G2阶段停滞细胞的能力。 最近，VPX的靶标已被确定为宿主限制因子SAMHD1，该因子是由VPX降解的。了解VPX和VPR的功能关系的进化分析表明，VPX和VPR具有重叠的函数。来自不同慢病毒的VPX蛋白以及一些慢病毒的VPR蛋白都有能力靶向其宿主物种的SAMHD1以降解。但是，HIV-1 VPR不与SAMHD1相互作用，因此这种病毒宿主相互作用的重要性仍然是一个谜。在这笔赠款中，我们将通过检查非洲绿猴及其慢病毒感染的自然感染研究中的宿主病毒进化来确定SAMHD1相互作用的重要性。此外，我们将确定VPX/VPR和SAMHD1如何通过确定来自不同灵长类动物宿主的SAMHD1蛋白通过不同VPX/VPR蛋白识别的分子基础来识别和逃脱。我们还将检查来自人类病原体HIV-2与人SAMHD1的VPX的相互作用，并将探讨某些HIV-1菌株还编码能够降解SAMHD1的VPR蛋白的可能性。最后，我们将测试以下假设：VPR和VPX的新功能通过确定VPR的祖先函数并确定某些VPR蛋白如何具有多个功能，从而在先前存在的功能上演变出来。