MODULATION OF CD8 T CELL FUNCTION BY HIV ENVELOPE PROTEI

HIV发病机制的特点是t细胞群的动态变化。虽然CD4 t细胞的群体异常已经被清楚地记录下来，但关于CD8 t细胞及其在HIV感染中的作用的信息却很少。CD8 t细胞通过其细胞毒性活性和释放可溶性HIV复制抑制剂在控制HIV复制中发挥关键作用。在HIV感染期间，CD8 t细胞凋亡增加，周转加速（端粒缩短），并且在感染过程后期数量大幅减少。CD8 t细胞也代表了hiv感染淋巴细胞间质性肺炎患者肺中存在的大多数浸润细胞，因此可能参与该疾病的过程。由于CD8 t细胞在控制HIV感染中的重要作用，我们正在研究HIV感染对CD8 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gp120在体外感染外周血单核细胞（PBMCs）时对CD8 t细胞产生间接的细胞病变作用。HIV介导的CD8 t细胞杀伤是巨噬细胞依赖性的，是HIV包膜蛋白通过CD8 t细胞上的趋化因子受体（CXCR4）发出信号的结果。在这里，我们建议扩展这些观察结果，并探索由于HIV感染而发生的CD8 t细胞修饰的谱。我们的具体目标是：(1)明确HIV包膜诱导CD8 t细胞凋亡的分子机制，强调CD4 t细胞在gp120趋化因子信号传导中的作用；(2)确定对CD8 t细胞凋亡至关重要的gp120决定因子，特别是gp120的表达和其他HIV趋化因子辅助受体的作用；(3)明确趋化因子和CD8 t细胞在hiv诱导的淋巴样间质性肺炎中的作用，特别强调gp120作为一种趋化因子，负责将CD8 t细胞募集到肺部；(4)明确HIV包膜蛋白诱导CD8 t细胞分化功能的全谱表型改变（mrna表达、趋化性、细胞溶解活性、趋化因子释放的变化）。我们预计这些实验将进一步加深我们对HIV感染期间发生的免疫功能障碍的理解，特别强调CD8 t细胞及其参与淋巴细胞间质性肺炎的发病机制和HIV感染的控制。

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.