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）疾病进展为获得性免疫缺陷综合征（AIDS）涉及为体液和细胞介导的免疫应答提供关键辅助活性的CD 4 + T细胞的丧失。尽管已经提出了多种机制来解释T细胞的耗竭，但gp 120对细胞存活的影响可能是多种的，并且不仅涉及免疫细胞，还涉及其他实质组织。本申请中提出的实验试图解决gp 120刺激的CXCR 4信号传导的分子基础和功能后果。本申请将测试以下假设：活化细胞中CXCR 4的gp 120连接启动PKC α、Lck、p38和Bim依赖性信号级联，导致线粒体损失！跨膜电位与随后的半胱天冬酶激活和凋亡（具体目标#1）;半胱天冬酶切割中间体直接反式激活NF-κ B介导的HIV-LTR转录（具体目标#2）;以及这些事件驱动体内CD 4消耗和HIV复制（具体目标#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).