Regulation of HIV-Mediated CD4 T Cell Apoptosis

描述(由申请人提供)：人类免疫缺陷病毒(HIV)疾病发展为获得性免疫缺陷疾病综合症(AIDS)涉及为体液和细胞介导的免疫反应提供关键辅助活动的CD4+T细胞的丧失。虽然已经提出了多种机制来解释T细胞的枯竭，但gp120对细胞存活的影响可能是多方面的，不仅涉及免疫细胞，还涉及其他实质组织。本申请中提出的实验试图解决gp120刺激的CXCR4信号的分子基础和功能后果。目前的应用将验证以下假设：在激活的细胞中，gp120连接CXCR4启动PKCA、Lck、p38和Bim依赖的信号级联，导致线粒体丢失！Caspase裂解中间产物直接反式激活核因子-kB介导的HIV-LTR转录(特异性目标2)；以及这些事件在体内驱动CD4耗竭和HIV复制(特异性目标3)。

DESCRIPTION (provided by applicant): Progression of Human Immunodeficiency Virus (HIV) disease to Acquired Immunodeficiency Disease Syndrome (AIDS) involves the loss of CD4+ T cells that provide critical helper activity for humoral and cell-mediated immune responses. Although multiple mechanisms have been proposed to account for the depletion of T cells, the effects of gp120 on cell survival are likely multiple, and involve not only immune cells, but other parenchymal tissues as well. Experiments proposed in this application seek to address the molecular basis and functional consequences of gp120-stimulated CXCR4 signaling. The present application will test the hypotheses: that gp120 ligation of CXCR4 in activated cells initiates PKCa, Lck, p38, and Bim-dependant signal cascade resulting in loss of mitochondria! transmembrane potential with consequent caspase activation and apoptosis (Specific Aim #1); that caspase cleavage intermediates directly transactivate NF-KB-mediated HIV-LTR transcription (Specific Aim #2); and that these events drive CD4 depletion and HIV replication in vivo (Specific Aim #3).