Procaspase 8 Activation by HIV Protease

HIV 蛋白酶激活半胱氨酸蛋白酶原 8

• 批准号: 6841913
• 负责人: ANDREW D BADLEY
• 金额: $ 25.81万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841913
• 关键词: HIV infections; SCID mouse; apoptosis; aspartic endopeptidases; clone cells; cysteine endopeptidases; cytotoxicity; enzyme activity; enzyme mechanism; helper T lymphocyte; human data; human immunodeficiency virus; nucleic acid sequence; protein protein interaction; tissue /cell culture; virus cytopathogenic effect; virus genetics; virus protein

DESCRIPTION (provided by applicant): It remains controversial as to how CD4+ T cells directly infected with HIV die following infection. Numerous mechanisms have been proposed to account for infected cell killing, however none of the proposed mechanisms are universally accepted. It has long been recognized that one HIV protein, HIV protease, is intrinsically cytotoxic as its expression causes the death of bacteria, yeast, and mammalian cells, however it remains unclear how HIV protease kills these cells. Experimental data now demonstrate that HIV protease cleaves host cell proteins in addition to viral proteins. Our laboratory has recently defined one mechanism by which HIV protease can kill cells; specifically HIV protease can cleave the apoptosis initiating protein, procaspase 8, to result in its activation. Thereafter, a traditional apoptosis cascade is initiated, ultimately resulting in the structural, nuclear, and morphologic changes associated with apoptosis. While we have demonstrated that this mechanism of HIV protease mediated killing can occur, we have yet to determine whether or not this mechanism does occur, particularly in vivo. The focus of the current proposal is to define the relevance of this form of cell killing both in infections, which occur in the test tube, as well as in patients. The clinical significance of this research may be reflected in recent clinical observations, suggesting an altered diseased course of patients who have infections with HIV that contain mutations within the HIV protease gene as compared to those that do not. We will explore the potential impact of these mutations by assessing the differential impact of wild type HIV protease versus mutant protease on procaspase 8 activation and cell killing.

描述（由申请人提供）：关于感染后CD4+ T细胞如何直接感染HIV死亡的CD4+ T细胞如何保持争议。已经提出了许多机制来解释受感染的细胞杀戮，但是所提出的机制均未普遍接受。长期以来，人们已经认识到，一种HIV蛋白HIV蛋白质在本质上是细胞毒性的，因为其表达会导致细菌，酵母和哺乳动物细胞的死亡，但是尚不清楚HIV蛋白酶如何杀死这些细胞。现在，实验数据表明，除病毒蛋白外，HIV蛋白酶除了裂解宿主细胞蛋白。我们的实验室最近定义了一种机制，艾滋病毒蛋白酶可以杀死细胞。特异性HIV蛋白酶可以裂解凋亡启动蛋白Procaspase 8，从而导致其激活。此后，启动了传统的凋亡级联反应，最终导致与凋亡相关的结构，核和形态变化。尽管我们已经证明了这种艾滋病毒蛋白酶介导的杀害的机制，但我们尚未确定是否确实发生了这种机制，尤其是在体内。当前建议的重点是定义这种形式的细胞杀死在试管中以及患者中发生的感染中的相关性。这项研究的临床意义可能反映在最近的临床观察结果中，这表明患有HIV感染的患者的病程改变了，与没有HIV蛋白酶基因中的突变相比，患有HIV感染的患者与不相比。我们将通过评估野生型HIV蛋白酶与突变蛋白酶对Procaspase 8激活和细胞杀伤的差异影响来探讨这些突变的潜在影响。