Regulation of HIV-Mediated CD4 T Cell Apoptosis

描述(由申请人提供)：公认的是，艾滋病毒感染导致CD4T细胞凋亡率加快，这是导致艾滋病毒感染者发生的CD4T细胞丢失的原因。HIV gp120还可以通过P38、JNK、Caspase和线粒体去极化等信号通路，触发包括CD4T细胞在内的多种细胞类型的凋亡。最后，人们普遍认为，HIV感染的巨噬细胞和树突状细胞产生的促凋亡配体(FasL和TRAIL)的增加，肠道上皮细胞的微生物移位，以及其他HIV蛋白包括Tat、Nef和VPR的细胞毒作用，都是导致HIV疾病期间CD4T细胞丢失的其他机制。目前尚不清楚的是，是否有一种共同的机制将这些不同的途径联系在一起。我们将提供原代CD4T细胞的初步数据，提示一种新的潜在机制，该机制连接了这些途径中的每一个，其中X4 gp120信号通过CXCR4首先通过改变microRNA的调节而导致易凋亡的CD4T细胞表型，从而FOXO3a被上调，并与JNK(也被gp120激活)一起被激活，导致包括BIM在内的凋亡调控分子的转录增强。这使得gp120启动的和易发生凋亡的细胞在遇到促凋亡刺激时发生凋亡，无论是FasL、TAT还是更多的gp120。特别值得注意的是，gp120刺激还具有通过上调Toll样受体机制，使CD4T细胞在暴露于细菌产物LPS后死亡的效果。鉴于gp120的广泛存在及其对HIV感染患者免疫调节的不同作用，检测有效抑制CXCR4的免疫效果是非常有意义的；因此，我们将仔细研究一类正在临床开发的新型CXCR4抑制剂KRH-1636的免疫和抗病毒效果。拟议的研究结果将提供信息并增加对艾滋病毒免疫发病机制的了解；微生物易位假说如何直接导致CD4T细胞丢失，以及临床努力开发一种无非靶标效应的CXCR4抑制剂。

DESCRIPTION (provided by applicant): It is well accepted that HIV infection causes an accelerated rate of CD4 T cell apoptosis that contributes to the CD4 T cell losses which occur in an HIV infected patient. It is also well accepted that HIV gp120 can trigger a variety of cell type including CD4 T cells to undergo apoptosis, using signaling pathways that involve P38, JNK, Caspases, and mitochondrial depolarization. Finally it is well accepted that other mechanisms contribute to CD4 T cell loss during HIV disease, including enhanced production of proapoptotic ligands (FasL and TRAIL) by HIV infected macrophages and dendritic cells, microbial translocation across the gut epithelia, and cytotoxic effects of other HIV proteins including Tat, Nef, and Vpr. What remains unknown is whether there is a common mechanism which ties these distinct pathways together. We will present preliminary data in primary CD4 T cells suggest a novel underlying mechanism which links each of these pathways, whereby X4 gp120 signaling through CXCR4 first causes an apoptosis prone phenotype of CD4 T cells by altering the regulation of microRNA, such that Foxo3A is upregulated, and together with JNK (also activated by gp120), Foxo3A is activated, resulting in enhanced transcription of apoptotic regulatory molecules including BIM. This then allows gp120 primed and apoptosis prone cells to undergo apoptosis when they encounter proapoptotic stimuli whether that be FasL, Tat, or more gp120. Of special interest, gp120 stimulation also has the effect of priming CD4 T cells to die following exposure to the bacterial product, LPS by virtue of upregulating the Toll like receptor machinery. Given the pervasive nature of gp120 and its diverse effects on the immune regulation of HIV infected patients, it is of great interest to examine the immune effects of effective CXCR4 inhibition; consequently we will carefully examine both the immune and antiviral effects of a new class of CXCR4 inhibitor which is in clinical development, KRH-1636. Results of the proposed investigations will both inform and increase the understanding of the immunopathogenesis of HIV; how the microbial translocation hypothesis directly causes CD4 T cell loss and the clinical efforts to develop a CXCR4 inhibitor that is free of off-target effects.