Regulation of HIV-Mediated CD4 T Cell Apoptosis

HIV 介导的 CD4 T 细胞凋亡的调节

• 批准号: 7547052
• 负责人: ANDREW D BADLEY
• 金额: $ 36.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547052
• 关键词: Accounting; Address; Apoptosis; Apoptotic; Binding; CD4 Positive T Lymphocytes; CXCR4 gene; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Conflict (Psychology); Data; Development; Disease; Event; GTP-Binding Proteins; Genetic Transcription; HIV; HIV Envelope Protein gp120; HIV Long Terminal Repeat; Immune; Immunologic Deficiency Syndromes; Induction of Apoptosis; Infection; Ligation; MAPK14 gene; Mediating; Membrane Potentials; Mitochondria; Molecular; Observational Study; Pathogenesis; Regulation; Secondary to; Signal Transduction; Source; Syndrome; T-Cell Depletion; Testing; Tissues; Virus Diseases; Virus Replication; acquired immunodeficiency; base; caspase-8; cell mediated immune response; in vivo; research study

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).

人免疫缺陷病毒（HIV）疾病的进展到获得性免疫缺陷疾病 综合征（AIDS）涉及CD4+ T细胞的丧失，这些细胞为体液和 细胞介导的免疫反应。尽管已经提出了多种机制来考虑 T细胞的耗竭，GP120对细胞存活的影响可能是多重的，不仅涉及 免疫细胞，但其他实质组织也是如此。本申请中提出的实验寻求 解决GP120刺激的CXCR4信号的分子基础和功能后果。这 当前的应用将检验假设：激活细胞中CXCR4的GP120结扎 PKCA，LCK，P38和BIM依赖性信号级联反应导致线粒体损失！跨膜 潜在的胱天冬酶激活和凋亡（特定目的＃1）；该胱天蛋白酶裂解 中间体直接反式激活NF-KB介导的HIV-LTR转录（特定AIM＃2）;那 这些事件在体内驱动CD4耗竭和HIV复制（特定目的＃3）。