MODULATION OF CD8 T CELL FUNCTION BY HIV ENVELOPE PROTEI

HIV 包膜蛋白对 CD8 T 细胞功能的调节

• 批准号: 6390540
• 负责人: Eric M. Verdin
• 金额: $ 26.72万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-16 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390540
• 关键词: HIV envelope protein gp120; HIV infections; apoptosis; biological signal transduction; chemokine; clinical research; cytotoxic T lymphocyte; diagnostic respiratory lavage; helper T lymphocyte; human tissue; molecular pathology; neutrophil; pathologic process; phenotype; pulmonary fibrosis /granuloma

HIV pathogenesis is characterized by dynamic changes in T-cell populations. While population abnormalities have been clearly documented in CD4 T-cells, less information is available on CD8 T-cells and on their part in HIV infection. CD8 T-cells play a critical role in the control of HIV replication by their cytotoxic activity and by the release of soluble inhibitors of HIV replication. During HIV infection, CD8 T-cells undergo increased apoptosis, demonstrate accelerated turnover (as reflected by telomere shortening), and decrease substantially in number late in the infection process. CD8 T-cells also represent the majority of infiltrating cells present in the lungs of HIV-infected patients with lymphocytic interstitial pneumonitis and are therefore likely to be involved in this disease process. Because of their important role in the control of HIV infection, we are investigating the effects of HIV infection on the differentiated functions and survival of CD8 T-cells. We recently observed that the HIV envelope protein, gp120, exerts indirect cytopathic effects on CD8 T-cells during infection of peripheral blood mononuclear cells (PBMCs) in vitro. HIV-mediated CD8 T-cell killing was macrophage-dependent and occurred as a result of signaling by HIV envelope protein via a chemokine receptor (CXCR4) on CD8 T-cells. Here we propose to expand on these observations and to explore the spectrum of CD8 T-cell modifications that occurs as a result of HIV infection. Our specific goals are: (1) To define the molecular mechanism of induction of CD8 T-cell apoptosis by the HIV envelope emphasizing the role of CD4 T-cells in chemokine signaling by gp120; (2) To identify the gp120 determinants that are critical for CD8 T-cell apoptosis and particularly gp120 presentation and role of other HIV chemokine coreceptors; (3) To define the role of chemokines and CD8 T-cells in HIV-induced lymphoid interstitial pneumonitis with a particular emphasis on the role of gp120 as a chemotactic factor responsible for the recruitment of CD8 T-cells to the lungs; (4) To define the full spectrum of phenotypic alterations induced by HIV envelope protein in CD8 T-cell differentiated functions (changes in mRNAs expression, chemotaxis, cytolytic activity, chemokine release). We anticipate that these experiments will further our understanding of the immune dysfunction that occurs during HIV infection with a particular emphasis on CD8 T-cells and their involvement in the pathogenesis of lymphocytic interstitial pneumonitis and the control of HIV infection.

HIV发病机制的特征在于T细胞群体的动态变化。 虽然在CD 4 T细胞中已经清楚地记录了群体异常，但关于CD 8 T细胞及其在艾滋病毒感染中的作用的信息较少。 CD 8 T细胞通过其细胞毒性活性和通过释放可溶性HIV复制抑制剂在控制HIV复制中起关键作用。 在HIV感染期间，CD 8 T细胞经历增加的凋亡，表现出加速的周转（如端粒缩短所反映的），并且在感染过程后期数量大幅减少。 CD 8 T细胞也代表了淋巴细胞性间质性肺炎的HIV感染患者肺中存在的大多数浸润细胞，因此可能参与该疾病过程。由于它们在控制HIV感染中的重要作用，我们正在研究HIV感染对CD 8 T细胞分化功能和存活的影响。 我们最近观察到，HIV包膜蛋白gp 120在体外感染外周血单个核细胞（PBMC）期间对CD 8 T细胞产生间接细胞病变效应。HIV介导的CD 8 T细胞杀伤是巨噬细胞依赖性的，并且是HIV包膜蛋白通过CD 8 T细胞上的趋化因子受体（CXCR 4）进行信号传导的结果。 在这里，我们建议扩展这些观察，并探讨由于HIV感染而发生的CD 8 T细胞修饰的谱。我们的具体目标是：（1）确定HIV包膜诱导CD 8 T细胞凋亡的分子机制，强调CD 4 T细胞在gp 120趋化因子信号转导中的作用;（2）鉴定对CD 8 T细胞凋亡至关重要的gp 120决定簇，特别是gp 120呈递和其他HIV趋化因子辅助受体的作用;（3）明确趋化因子和CD 8 T细胞在HIV诱导的淋巴间质性肺炎中的作用，特别强调gp 120作为负责向肺募集CD 8 T细胞的趋化因子的作用;（4）明确HIV包膜蛋白在CD 8 T细胞分化功能中诱导的表型改变的全谱（mRNA表达、趋化性、细胞溶解活性、趋化因子释放的改变）。 我们预计，这些实验将进一步我们的免疫功能障碍，发生在HIV感染，特别强调CD 8 T细胞及其参与的淋巴细胞性间质性肺炎的发病机制和HIV感染的控制的理解。