Role Of Hiv Envelope Protein In Replication/Pathogenesis

HIV包膜蛋白在复制/发病机制中的作用

• 批准号: 6507017
• 负责人: Anthony S. Fauci
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6507017
• 关键词: HIV envelope protein gp120; HIV infections; apoptosis; biological signal transduction; cysteine endopeptidases; cytokine; cytokine receptors; enzyme activity; genetic transcription; helper T lymphocyte; human immunodeficiency virus 1; human tissue; macrophage; microarray technology; microorganism culture; oligonucleotides; pathologic process; receptor binding; virus genetics; virus receptors; virus replication

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.

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。我们特别感兴趣的是包膜受体相互作用如何影响病毒复制和艾滋病毒相关的免疫系统功能障碍。 HIV包膜蛋白在原代T细胞和巨噬细胞中诱导多种生物反应，从诱导促炎细胞因子到增加细胞凋亡率。值得注意的是，其中许多反应与艾滋病毒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，我们还证明 HIV 的包膜刺突 gp120 会诱导 Caspase-3 和 Caspase-6 的激活。这两种酶在诱导细胞凋亡中起着关键作用。在这方面，我们提供了与艾滋病毒引起的免疫功能障碍的起源相关的重要信息。 我们的主要目标之一是全面定义 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常常与基因表达的变化相关。在这方面，我们采用高密度寡核苷酸微阵列来识别总 PBMC 和巨噬细胞转录模式的变化。我们使用的微阵列包含 10,000 多个基因，包括目前在 GENBANK 中编目的所有序列。利用这项强大的新技术，我们已经确定了人类免疫系统对 HIV-1 包膜的许多先前未描述的反应。我们正在研究这些分析中确定的基因与 HIV-1 相关免疫功能障碍的潜在相关性。