Role of Chemokine & T-Cell Receptors in HIV Pathogenesis

描述（申请人提供）：hiv包膜蛋白gp120在触发t淋巴细胞凋亡中起关键作用，这是hiv介导的免疫功能障碍的主要致病特征。T细胞凋亡也是一个生理过程，在稳态和T细胞成熟过程中调节抗原受体库的选择。我们假设gp120诱导的t细胞受体（TCR）和趋化因子受体信号通路之间的串扰导致细胞凋亡。我们关于TCR信号成分CD45和SLP-76在hiv -gpl20诱导的细胞凋亡中的作用的初步数据支持了这一假设。此外，我们最近发现TCR和趋化因子受体CXCR4之间的串导通过AKT/蛋白激酶B （PKB）、热休克蛋白70 （HSP-70）、caspase-1和RIP2 （caspase募集结构域含丝氨酸/苏氨酸激酶）介导的新机制调节细胞凋亡。为了分析TCR成分和趋化因子受体CXCR4/CCR5调节gp120诱导的细胞凋亡的机制，我们将追求以下具体目标：目的1)我们将通过定义CD45的结构域和表征负责细胞凋亡的CD45信号传导来评估CD45和CXCR4/CCR5信号分子之间的相互作用。目的2)我们将对tcr介导的介导Ca2+依赖性凋亡通路的下游效应物SLP-76进行结构和功能分析。Aim 3)我们将分析AKT/HSP-70凋亡通路可能导致叉头转录因子的诱导作用，并将表征caspase-1的激活及其受RIP2的调控。我们也在探索抑制gp120诱导的细胞凋亡的创新策略。在这方面，我们已经证明了一种新的蛋白，Slit，与Robo受体结合并调节CXCR4功能，可以抑制gp120诱导的细胞凋亡。目的4)我们将确定Slit/Robo复合体中的哪些结构域调节观察到的抗凋亡作用。这些研究旨在确定凋亡信号分子和参与t细胞损失的效应途径，从而为对抗艾滋病免疫缺陷提供新的治疗靶点。

DESCRIPTION (provided by applicant): The HIV-envelope protein gp120 plays a critical role in triggering the apoptosis of T-lymphocytes, which is a central pathogenic feature of HIV-mediated immune dysfunction. T-cell apoptosis is also a physiological process that regulates antigen receptor repertoire selection during homeostasis and the maturation of T- cells. We hypothesize that gp120-induced cross-talk between T-cell receptor (TCR) and chemokine receptor signaling pathways leads to apoptosis. Our preliminary data on the role of the TCR signaling components CD45 and SLP-76 in HIV-gpl20-induced apoptosis support this hypothesis. In addition, we have recently shown that cross-talk between TCR and chemokine receptor CXCR4 regulates apoptosis via a novel mechanism that is mediated by AKT/Protein Kinase B (PKB), heat shock protein-70 (HSP-70), caspase-1 and RIP2 (caspase recruitment domain-containing serine/threonine kinase). To analyze mechanistically how the TCR components and chemokine receptors CXCR4/CCR5 regulate gp120-induced apoptosis, we will pursue the following specific aims: Aim 1) we will assess the interaction between CD45 and CXCR4/CCR5 signaling molecules by defining the domain of CD45 and characterizing the CD45 signaling responsible for apoptosis. Aim 2) we will perform structural and functional analyses of the TCR-mediated downstream effector SLP-76 that mediates Ca2+dependent apoptotic pathways. Aim 3) we will analyze the role of the AKT/HSP-70 apoptotic pathway that may lead to the induction of forkhead transcription factors, and will characterize the activation of caspase-1 and its regulation by RIP2. We are also exploring innovative strategies to inhibit gp120-induced apoptosis. In this regard, we have shown that a novel protein, Slit, which binds to the Robo receptor and modulates CXCR4 function can inhibit gp120-induced apoptosis. Aim 4) we will identify which domains in the Slit/Robo complex regulate the observed anti-apoptotic effects. These studies are designed to identify apoptotic signaling molecules and effector pathways involved in T-cell loss, and thus to provide novel therapeutic targets to combat immune deficiency in AIDS.