Role Of Hiv Envelope Protein In Replication/Pathogenesis

该项目的主要目标是定义和表征HIV-1包膜介导的信号对CD4+ t细胞和巨噬细胞的影响。我们对包膜受体相互作用如何影响病毒复制和HIV相关的免疫系统功能障碍特别感兴趣。HIV包膜蛋白在原代t细胞和巨噬细胞中诱导一系列生物反应，从诱导促炎细胞因子到增加细胞凋亡率。值得注意的是，许多这些反应与与HIV疾病相关的免疫功能障碍有关。我们已经证明HIV包膜通过CCR5诱导信号，CCR5是HIV与CD4+ T细胞和巨噬细胞结合的重要共受体。此外，我们已经证明gp120， HIV的包膜尖峰，诱导Caspase-3和Caspase-6的激活。这两种酶在诱导细胞凋亡中起关键作用。在这方面，我们提供了与HIV诱导的免疫功能障碍的起源有关的重要信息。我们的主要目标之一是全局定义CD4+淋巴细胞和巨噬细胞对包膜介导的信号传导的反应。细胞功能的重要变化通常与基因表达的变化有关。在这方面，我们采用高密度寡核苷酸微阵列来鉴定总pbmc和巨噬细胞转录模式的变化。我们使用的微阵列包含超过10,000个基因，包括目前在GENBANK中编目的所有序列。利用这项强大的新技术，我们已经确定了许多以前未描述的人类免疫系统对HIV-1包膜的反应。我们正在研究这些分析中发现的基因与HIV-1相关免疫功能障碍的潜在相关性。

The principle objective of this project is to define and characterize the consequences of HIV-1 envelope mediated signals on CD4+ T-cells and macrophages. We are specifically interested in how envelope-receptor interactions influence viral replication and HIV associated immune system dysfunction. HIV envelope proteins induce a number of biological responses in primary T-cells and macrophages ranging from the induction of pro-inflammatory cytokines to increased rates of apoptosis. Of note, many of these responses correlate with the immune dysfunction associated with HIV disease. We have demonstrated that HIV envelope induces signals through CCR5, an important co-receptor for the binding of HIV to CD4+ T cells and macrophages. In addition, we have demonstrated that gp120, the envelope spike of HIV, induces the activation of Caspase-3 and Caspase-6. These two enzymes play a critical role in the induction of apoptosis. In this regard we have provided important information relevant to the origin of HIV induced immune dysfunction. One of our principle objectives is to globally define the response of both CD4+ lymphocytes as well as macrophages to envelope mediated signaling. Important changes in cell function are frequently associated with changes in gene expression. In this regard we have employed high density oligonucleotide microarrays to identify changes in transcriptional patterns of total PBMCs and macrophages. The microarrays we are employing encompass more than 10,000 genes, including all sequences currently catalogued in GENBANK. Utilizing this powerful new technology we have identified a number of previously undescribed responses of the human immune system to HIV-1 envelope. We are investigating the genes identified in these analyses for their potential relevance to HIV-1 associated immune-dysfunction.