Functional Characterization of the Hepatitis C Virus E1-E2 Glycoproteins
丙型肝炎病毒 E1-E2 糖蛋白的功能表征
基本信息
- 批准号:7897844
- 负责人:
- 金额:$ 3.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-22 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsBindingBiological AssayBiological ModelsCell fusionCell membraneCell surfaceCellsCellular MembraneChimeric ProteinsClathrinEndocytosisEndosomesFailureFluorescence MicroscopyGenus AlpharetrovirusGlycoproteinsHIVHepatitis CHepatitis C virusImageIncubatedIndividualInfectionInfection preventionKineticsLightMeasuresMediatingMembraneMethodologyModelingMonitorNucleocapsidPathway interactionsPrevention strategyProcessRetroviral VectorSiteStagingStressTemperatureTestingTimeVaccinesViralViral Fusion ProteinsViral GenomeVirusVirus InactivationVirus ReceptorsWorkbasebeta-Lactamasedesigneffective therapyinsightnovel virusparticlepathogenpublic health relevancereceptorreceptor bindingresearch studytraffickinguptake
项目摘要
DESCRIPTION (provided by applicant): The hepatitis C virus (HCV) is an important pathogen that has infected approximately 170 million people worldwide. In spite of extensive efforts, surprisingly little is known about the mechanism by which HCV initiates infection. The lack of vaccine or effective therapy against this virus stresses the urgent need for studies of HCV entry into host cells. HCV is an enveloped virus that enters cells via a clathrin-mediated pathway and releases its nucleocapsid by fusing the viral membrane with an endosomal membrane a process that is promoted by HCV E1 and E2 glycoproteins. The fusion induced by E1E2 is strictly receptor- and low pH-dependent. Not only is the mechanism of this process poorly understood, but even the identity of the fusion protein (E1 vs. E2) has not been established. This is due to the lack of a tractable model system to study HCV fusion. Our working hypothesis is that HCV fusion precedes through at least two major steps - a priming step through interactions with cellular receptors which render E1E2 fusogenic, followed by low pH-dependent fusion. This hypothesis predicts that: (1) low pH pre-treatment in the absence of receptors does not induce irreversible conformational changes in E1E2 leading to virus inactivation; (2) binding to soluble or to membrane-anchored receptors renders E1E2 competent to undergo conformational changes and promote fusion at low pH. These predictions will be tested using novel virus inactivation, virus-cell fusion and cell-cell fusion assays. Time-resolved imaging of single virus will be implemented for tracking HCV uptake and subsequent fusion with an endosome. HCV entry will be further examined by capturing and characterizing distinct intermediate stages of fusion. These experiments should provide new insights into the mechanism of E1E2-induced fusion and might help to design preventive strategies to block HCV infection. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) is an important pathogen that has infected over 170 million people worldwide. Following HCV internalization by a cell, infection is initiated by merging of viral and cellular membranes that releases the viral genome. To elucidate the mechanism of membrane merger mediated by HCV glycoproteins, single virus entry into a host cell will be visualized by real-time by fluorescence microscopy. Understanding the virus entry process will suggest new strategies to prevent infection.
描述(由申请人提供):丙型肝炎病毒(HCV)是一种重要的病原体,已感染全球约1.7亿人。尽管广泛的努力,令人惊讶的是,很少有人知道的机制,HCV启动感染。由于缺乏针对该病毒的疫苗或有效的治疗方法,迫切需要研究HCV进入宿主细胞的机制。HCV是一种包膜病毒,通过网格蛋白介导的途径进入细胞,并通过将病毒膜与内体膜融合释放其核衣壳,该过程由HCV E1和E2糖蛋白促进。E1 E2诱导的融合是严格的受体和低pH依赖性的。不仅是这个过程的机制知之甚少,但即使是融合蛋白(E1与E2)的身份还没有建立。这是由于缺乏一个易于处理的模型系统来研究HCV融合。我们的工作假设是,HCV融合之前,通过至少两个主要步骤-一个启动步骤,通过与细胞受体的相互作用,使E1 E2融合,其次是低pH值依赖性融合。这一假设预测:(1)在不存在受体的情况下进行低pH预处理不会诱导E1 E2发生不可逆转的构象变化,从而导致病毒灭活;(2)与可溶性或膜锚定受体的结合使E1 E2能够发生构象变化并促进低pH下的融合。这些预测将使用新型病毒灭活、病毒-细胞融合和细胞-细胞融合试验进行测试。将实施单个病毒的时间分辨成像以跟踪HCV摄取和随后与内体的融合。将通过捕获和表征融合的不同中间阶段来进一步检查HCV进入。这些实验将为E1 E2诱导的融合机制提供新的见解,并可能有助于设计阻断HCV感染的预防策略。公共卫生相关性:丙型肝炎病毒(HCV)是一种重要的病原体,已感染全球超过1.7亿人。在HCV被细胞内化后,通过病毒和细胞膜的合并释放病毒基因组来启动感染。为了阐明HCV糖蛋白介导的膜合并机制,将通过荧光显微镜实时观察单个病毒进入宿主细胞。了解病毒进入过程将提出预防感染的新策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gregory B Melikian其他文献
Gregory B Melikian的其他文献
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{{ truncateString('Gregory B Melikian', 18)}}的其他基金
Molecular Interactions of HIV-1 with the Nuclear Pore Complex
HIV-1 与核孔复合物的分子相互作用
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- 资助金额:
$ 3.7万 - 项目类别:
Molecular Interactions of HIV-1 with the Nuclear Pore Complex
HIV-1 与核孔复合物的分子相互作用
- 批准号:
10462620 - 财政年份:2019
- 资助金额:
$ 3.7万 - 项目类别:
Inhibition of viral entry by interferon-induced proteins
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10418696 - 财政年份:2018
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$ 3.7万 - 项目类别:
Functional Characterization of the Hepatitis C Virus E1-E2 Glycoproteins
丙型肝炎病毒 E1-E2 糖蛋白的功能表征
- 批准号:
7522862 - 财政年份:2009
- 资助金额:
$ 3.7万 - 项目类别:
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