REGULATION OF HIV MEDIATED CD4 T CELL APOPTOSIS

描述：(改编自申请人的摘要)导致 HIV感染者体内的CD4T细胞耗竭仍有待确定。 某些病毒感染，包括艾滋病毒感染，会导致慢性 免疫系统的激活状态，导致增强状态 对多种免疫细胞的凋亡易感性。此外，艾滋病毒 感染特别会引发更高水平的易感性 外周CD4T细胞Fas依赖性细胞凋亡的研究第二个HIV特异性病毒 后遗症是诱导抗原提呈细胞表达FasL 例如巨噬细胞。基于优惠和具体的互动 在CD4T细胞和巨噬细胞之间，这项提议将解决 Fas易感的CD4T细胞与FasL相遇假说 表达巨噬细胞会导致CD4T细胞的选择性耗尽。 初步数据显示，这两种机制都增加了易感性 对CD4T细胞Fas的作用，以及巨噬细胞FasL表达的增加 不仅在体外模型中观察到，而且在艾滋病毒感染患者中观察到。 了解调节原发性高血压易感性的分子机制 CD4T细胞对Fas依赖性细胞凋亡的影响(Aim I)，并鉴定 HIV依赖机制对巨噬细胞FasL表达的调节 (AIM II)将用于测试艾滋病毒感染患者的相关性(AIM III)。 这三个目标的结果应该建立临床相关性 HIV诱导的Fas/FasL相互作用失调是CD4T细胞的一个原因 人类免疫缺陷病毒感染者体内的能量消耗。

DESCRIPTION: (Adapted from applicant's abstract) The mechanisms leading to CD4 T cell depletion in HIV-infected individuals remain to be determined. Certain viral infections including HIV infection lead to a chronic activation state of the immune system that results in an enhanced state of susceptibility to apoptosis in a variety of immune cells. In addition, HIV infection specifically triggers an enhanced level of susceptibility to Fas-dependent apoptosis in peripheral CD4 T cells. A second HIV specific sequelae is the induction of FasL expression in antigen presenting cells such as macrophages. Based on the preferential and specific interaction between CD4 T cells and macrophages, this proposal will address the hypothesis that encounter of the Fas susceptible CD4 T cell with a FasL expressing macrophage leads to selective depletion of the CD4 T cells. Preliminary data demonstrate that both mechanisms, increased susceptibility to Fas in CD4 T cells, and increased FasL expression in macrophages, is observed not only in in vitro models but in HIV-infected patients. Understanding the molecular mechanisms regulating susceptibility of primary CD4 T cells to Fas-dependent apoptosis (Aim I), and identifying the regulation of FasL expression in macrophages by HIV-dependent mechanisms (Aim II) will be used to test relevance in HIV-infected patients (Aim III). Results from these three aims should establish the clinical relevance of the HIV induced dysregulation of Fas/FasL interactions as a cause of CD4 T cell depletion in HIV-infected patients.