Regulation of HIV-Mediated CD4 T Cell Apoptosis

人类免疫缺陷病毒病向获得性免疫缺陷病的进展 综合征(艾滋病)涉及为体液和血液提供关键辅助活动的CD4+T细胞的丧失 细胞介导的免疫反应。尽管已经提出了多种机制来解释 T细胞的耗竭，gp120对细胞存活的影响可能是多方面的，而且不仅涉及 免疫细胞，但也包括其他实质组织。本申请中提出的实验旨在 阐述gp120刺激的CXCR4信号的分子基础和功能后果。这个 目前的应用将检验这些假设：活化细胞中的cxCR4的gp120连接启动 PKCA、LCK、p38和Bim依赖的信号级联导致线粒体丢失！跨膜 Caspase激活和凋亡的可能性(特定目标1)；caspase裂解 中间体直接反式激活核因子-KB介导的HIV-LTR转录(特定目的#2)； 这些事件导致体内的CD4耗尽和HIV复制(特定目标3)。

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).