Regulation of HIV-Mediated CD4 T Cell Apoptosis

人类免疫缺陷病毒（HIV）疾病进展为获得性免疫缺陷病 综合征（艾滋病）涉及CD 4 + T细胞的损失，这些细胞为体液免疫和免疫调节提供关键的辅助活性。 细胞介导的免疫反应。虽然已经提出了多种机制来说明 由于T细胞的耗竭，gp 120对细胞存活的影响可能是多方面的，不仅涉及 免疫细胞，还有其他实质组织。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。的 本申请将检验以下假设：活化细胞中CXCR 4的gp 120连接启动了 PKCa、Lck、p38和Bim依赖性信号级联导致线粒体丢失！跨膜 潜在的随后的半胱天冬酶激活和凋亡（具体目标#1）;半胱天冬酶裂解 中间体直接反式激活NF-κ B介导的HIV-LTR转录（特异性目的#2）;并且 这些事件驱动体内CD 4耗竭和HIV复制（具体目标#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).