HIV/SIV Vpx-Invariant chain Interaction

描述(申请人提供)：在我们对HIV-2病毒蛋白X(VPX)的研究过程中，我们偶然发现VPX与不变链(LI)相互作用，并在VPX转基因细胞和HIV-2感染细胞中丢失LI表达。因此，拟议的研究将调查这一观察对于理解HIV-2和SIVmac发病机制的重要性。 1.VPX与不变链的相互作用 我们发现VPX与人类不变链(LI)相互作用，导致抗原提呈细胞中LI的耗竭。拟议的研究将通过进一步定义相互作用的序列和检查VPX对抗原呈递到CD4+T细胞的影响来进一步确定这一观察的意义。 2.VPX活性在体内的意义 VPX已被证明是SLVmac在阴道内暴露后建立感染的关键。目前尚不清楚这是由于VPX与LI和缺陷的CD4+辅助T细胞反应的相互作用，还是由于VPX介导的静止细胞前整合复合体的核输入缺陷，或者是VPX的这两个特性，或者两者都不是。我们将绘制SIVmac VPX的结构域，这些结构域对核定位和Li相互作用至关重要。选择性地错过每个活性的突变体SIVmac VPX将通过感染恒河猴进行研究。

DESCRIPTION (provided by applicant): During the course of our studies of HIV-2 viral protein X (Vpx), we made the serendipitous discovery of Vpx interaction with invariant chain (li), and loss of li expression in Vpx transfected and HIV-2 infected cells. Therefore, the proposed studies will investigate the importance of this observation with regards to understanding the pathogenesis of HIV-2 and SIVmac. 1. Interaction of Vpx with invariant chain - We have found that Vpx interacts with human invariant chain (li), resulting in depletion of li from antigen-presenting cells. The proposed studies will further define the significance of this observation by further definition of the interacting sequences and examining the effects of Vpx on antigen presentation to CD4+ T cells. 2. Significance of Vpx activities in vivo Vpx has been shown to be critical for SlVmac to establish infection after intravaginal exposure. It is unclear whether this is due to interaction of Vpx with li and defective CD4+ helper T cell responses, defective Vpx-mediated nuclear import of the preintegration complex of quiescent cells, or both of these properties of Vpx, or neither property. We will map the domains of SIVmac Vpx that are critical for nuclear localization and li interaction. Mutant SIVmac Vpx selectively missing each activity will then be studied by infection of rhesus macaques.