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.

该项目的主要目的是定义和表征HIV-1包膜在CD4+ T细胞和巨噬细胞上介导的信号的后果。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许多生物学反应，从促炎性细胞因子诱导到凋亡率增加。值得注意的是，其中许多反应与与HIV疾病有关的免疫功能障碍相关。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，我们已经证明了HIV的包膜尖峰GP120诱导caspase-3和caspase-6的激活。这两种酶在诱导凋亡中起关键作用。在这方面，我们提供了与HIV诱导的免疫功能障碍起源有关的重要信息。 我们的主要目标之一是在全球范围内定义CD4+淋巴细胞的响应以及巨噬细胞对包膜介导的信号传导的响应。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，我们采用了高密度寡核苷酸微阵列来确定总PBMC和巨噬细胞的转录模式的变化。我们采用的微阵列包含10,000多个基因，包括当前在GenBank中分类的所有序列。利用这种强大的新技术，我们已经确定了人类免疫系统对HIV-1信封的许多先前未描述的反应。我们正在研究这些分析中鉴定的基因与HIV-1相关免疫功能的潜在相关性。