The Evolution of Vpr/Vpx Function in Primate Lentiviruses

描述（由申请人提供）：HIV-1和其他灵长类慢病毒编码辅助基因，用于增强病毒复制和抵消宿主抗病毒因子。这些限制因子具有限制病毒复制和影响慢病毒跨物种传播的能力。此外，病毒辅助蛋白和宿主限制因子之间的相互作用是新型药物干预HIV治疗的潜在来源。Vpx和Vpr是两种相关的慢病毒辅助蛋白。虽然所有灵长类慢病毒都编码Vpr，但其中只有两种也编码Vpx。Vpx对于灵长类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具有许多功能，包括在细胞周期的G2期阻止细胞的能力。最近，Vpx的靶点被确定为宿主限制因子SAMHD1，它是Vpx降解的靶点。对Vpx和Vpr功能关系的进化分析表明，Vpx和Vpr具有重叠的功能。来自不同慢病毒的Vpx蛋白以及一些慢病毒的Vpr蛋白都有能力靶向宿主物种的SAMHD1进行降解。然而，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。在这项资助中，我们将通过在非洲绿猴及其慢病毒感染的自然感染研究中检查宿主-病毒进化来确定SAMHD1相互作用的重要性。此外，我们将通过确定来自不同灵长类宿主的SAMHD1蛋白被不同Vpx/Vpr蛋白识别的分子基础，确定Vpx/Vpr和SAMHD1如何共同进化以识别和逃避彼此。我们还将研究来自人类病原体HIV-2的Vpx与人类SAMHD1的相互作用，并将探索一些HIV-1菌株也编码能够降解SAMHD1的Vpr蛋白的可能性。最后，我们将通过确定Vpr的祖先功能和确定一些Vpr蛋白如何具有多种功能来验证Vpr和Vpx的新功能是在原有功能的基础上进化而来的这一假设。

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.