REGULATION OF HIV MEDIATED CD4 T CELL APOPTOSIS

HIV 介导的 CD4 T 细胞凋亡的调节

• 批准号: 6169900
• 负责人: CARLOS V PAYA
• 金额: $ 24.14万
• 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 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169900
• 关键词: CD95 molecule; DNA binding protein; HIV infections; apoptosis; biological signal transduction; genetic transcription; helper T lymphocyte; human tissue; macrophage; pathologic process; tissue /cell culture; transfection

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.

描述：（改编自申请人的摘要） HIV感染者的CD 4 T细胞耗竭仍有待确定。 某些病毒感染，包括艾滋病毒感染，导致慢性 免疫系统的激活状态，导致增强的 在多种免疫细胞中对凋亡的易感性。 此外，艾滋病毒 感染特异性地触发对以下疾病的敏感性增强 外周血CD 4 T细胞Fas依赖性凋亡 第二种艾滋病毒特异性 后遗症是在抗原呈递细胞中诱导FasL表达 如巨噬细胞。 基于优先和特定的相互作用 在CD 4 T细胞和巨噬细胞之间，这项提案将解决 Fas易感性CD 4 T细胞与FasL相遇假说 表达巨噬细胞导致CD 4 T细胞的选择性耗竭。 初步数据表明，这两种机制，增加易感性， 与CD 4 T细胞中Fas的结合，以及巨噬细胞中FasL表达的增加， 不仅在体外模型中观察到，而且在HIV感染患者中观察到。 了解调节原发性肝癌易感性的分子机制 CD 4 T细胞对Fas依赖性凋亡的影响（Aim I），并鉴定 HIV依赖性机制对巨噬细胞FasL表达的调节 (Aim II）将用于测试HIV感染患者的相关性（目的III）。 这三个目标的结果应确立 HIV诱导的Fas/FasL相互作用失调是CD 4 T细胞凋亡的原因 艾滋病病毒感染者的消耗。