Mechanism of HCV Internalization into Target Cells

HCV 内化至靶细胞的机制

• 批准号: 7140368
• 负责人: TATJANA DRAGIC
• 金额: $ 20.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140368
• 关键词: bioassay; caveolins; clathrin; endocytosis; glycoproteins; hepatitis C; hepatitis C virus; host organism interaction; human immunodeficiency virus 1; liver cells; receptor binding; transfection /expression vector; virus infection mechanism; virus protein; virus receptors

DESCRIPTION (provided by applicant): It is estimated that 2% of the world's population is infected with Hepatitis C virus (HCV) and at risk of developing life-threatening liver disease. A major goal of HCV research is to understand how this virus selectively targets hepatocytes and perhaps also certain lymphocytes, but lack of appropriate experimental models has greatly limited studies of viral tropism and entry. A major advance in the field has been the recent discovery that retroviral particles pseudotyped with HCV envelope glycoproteins authentically replicate the early stages of the viral life cycle. Based on our recent studies using this novel experimental system, we postulate that HCV envelope glycoproteins bind to a receptor and subsequently to a co-receptor (CD81), which leads to internalization of viral particles and low pH-dependent fusion with intracellular membranes. Surprisingly, we discovered that HCV envelope glycoproteins cannot induce receptor-mediated, low pH-dependent fusion at the cell surface, indicating that intracellular factors critically modulate post-attachment steps of viral entry. Ongoing studies in our laboratory aim to elucidate the viral and cellular factors that regulate the unique and complex cascade of events resulting in HCV fusion with target cell membranes. Here, we propose to determine the basic mechanism of HCV internalization and trafficking to fusion-competent intracellular compartments. In the long term, we plan to identify the intracellular factors that allow HCV entry to occur in specific organelles. The entry stage of viral replication constitutes a target for neutralizing antibodies as well as pharmacologic agents. A detailed understanding of the downstream events leading to viral entry is therefore critical and may yield additional targets for preventive or therapeutic intervention. These studies will significantly advance our understanding of the mechanism by which HCV enters liver cells and will serve as a foundation for developing specific inhibitors that target this key step of viral replication.

描述（由申请人提供）： 据估计，世界上有 2% 的人口感染丙型肝炎病毒 (HCV)，并面临患上危及生命的肝病的风险。 HCV 研究的一个主要目标是了解这种病毒如何选择性地靶向肝细胞，或许还有某些淋巴细胞，但缺乏适当的实验模型极大地限制了病毒趋向性和进入的研究。该领域的一项重大进展是最近发现，用 HCV 包膜糖蛋白假型化的逆转录病毒颗粒能够真实地复制病毒生命周期的早期阶段。基于我们最近使用这种新型实验系统的研究，我们假设 HCV 包膜糖蛋白与受体结合，随后与辅助受体 (CD81) 结合，从而导致病毒颗粒的内化以及与细胞内膜的低 pH 依赖性融合。令人惊讶的是，我们发现HCV包膜糖蛋白不能在细胞表面诱导受体介导的、低pH依赖性融合，这表明细胞内因子关键地调节病毒进入的附着后步骤。我们实验室正在进行的研究旨在阐明调节导致 HCV 与靶细胞膜融合的独特而复杂的级联事件的病毒和细胞因素。在这里，我们建议确定 HCV 内化和运输到具有融合能力的细胞内区室的基本机制。从长远来看，我们计划确定允许丙型肝炎病毒进入特定细胞器的细胞内因素。病毒复制的进入阶段构成中和抗体以及药物制剂的目标。因此，详细了解导致病毒进入的下游事件至关重要，并且可能会产生预防或治疗干预的额外目标。这些研究将显着增进我们对丙型肝炎病毒进入肝细胞机制的理解，并将为开发针对病毒复制这一关键步骤的特异性抑制剂奠定基础。