Hepatitis C virus infection and lipoproteins

丙型肝炎病毒感染与脂蛋白

• 批准号: 7483151
• 负责人: GUANGXIANG George LUO
• 金额: $ 21.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483151
• 关键词: Accounting; Antibodies; Antiviral Agents; Antiviral Therapy; Apolipoproteins; Apolipoproteins B; Appendix; Biochemical; Biological; Blocking Antibodies; Cell Culture System; Cell Surface Receptors; Cells; Chemicals; Culture Media; Density Gradient Centrifugation; Detection; Foundations; Genome; Goals; Health; Hepatitis C; Hepatitis C virus; High Density Lipoproteins; Human; Infection; Infectious hepatitides; Intervention; Investigation; Lipoproteins; Low-Density Lipoproteins; Mediation; Molecular; Nature; Numbers; Pharmaceutical Preparations; Play; Production; Property; Proteomics; RNA; Range; Role; System; Time; United States; Very low density lipoprotein; Virion; Virus; Virus Assembly; Virus Replication; anti-hepatitis C; base; concept; density; drug discovery; expression vector; inhibitor/antagonist; novel; particle; receptor; research study; viral RNA; virus culture

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection poses a major global health problem, infecting approximately 4 million people in the United States and 170 million people worldwide. The properties and biochemical composition of HCV virions have not been determined due largely to the lack of a robust culture system for HCV infection and propagation. Recently, we have successfully established a stable culture system for robust production of infectious HCV. The characterization of HCV RNA-containing particles revealed that the low-density HCV particles were of the highest infectivity in sharp contrast to the higher-density particles, which contained the highest level of HCV RNA genome but were not infectious. Additionally, apolipoproteins B and E were detected in the low- density fractions of HCV particles, and HCV infection was potently inhibited by human lipoproteins LDL and VLDL. Therefore, we hypothesize that HCV virion is assembled with lipoproteins, which play important roles in the mediation of HCV infection through specific interactions with cell surface receptors/co-receptors. HCV virion assembly with lipoproteins represents a novel concept that warrants exploratory investigation and holds promise for discovering novel antiviral drugs. The overall goal of this application is to determine the properties and biochemical composition of HCV RNA-containing particles and to define the role of lipoproteins in HCV assembly and infection. Our specific aims are: 1) to determine the nature and biochemical composition of HCV RNA-containing particles and the structural determinants of HCV infectivity using structural, cell biological, biochemical, immunological, and proteomic approaches; 2) to define the role of lipoproteins in HCV virion production and infection by altering the levels of lipoprotein production in stable HCV-producing cells as well as by using antibodies against specific apolipoproteins. The levels of lipoproteins will be either up regulated by apolipoprotein-expression vectors and chemical inducers or down regulated by specific siRNAs and small molecular inhibitors. Additionally, we will determine the underlying mechanisms for the inhibition of HCV infection by human lipoproteins. Findings derived from these studies will not only determine the molecular basis underlying HCV infectivity but also provide novel targets for antiviral intervention. Furthermore, information gained from our studies will provide a foundation towards a thorough understanding of the molecular mechanisms of HCV virion assembly and infection. Hepatitis C virus (HCV) infection poses a major global health problem, infecting about 4 million people in the United States and 170 million people worldwide. This application is to determine the properties and biochemical composition of HCV particles and to define the role of lipoproteins in HCV production and infection. Findings derived from these studies will provide novel targets and therapies for antiviral intervention of HCV infection.

描述（由申请人提供）：丙型肝炎病毒 (HCV) 感染构成了一个重大的全球健康问题，感染了美国约 400 万人和全球 1.7 亿人。 HCV 病毒体的特性和生化组成尚未确定，主要是由于缺乏用于 HCV 感染和繁殖的强大培养系统。最近，我们成功建立了稳定的培养系统，用于大量生产传染性丙型肝炎病毒。含HCV RNA颗粒的表征表明，低密度HCV颗粒具有最高的感染性，与高密度颗粒形成鲜明对比，高密度颗粒含有最高水平的HCV RNA基因组，但不具有感染性。此外，在HCV颗粒的低密度部分中检测到载脂蛋白B和E，并且HCV感染被人脂蛋白LDL和VLDL有效抑制。因此，我们假设HCV病毒体由脂蛋白组装而成，脂蛋白通过与细胞表面受体/共受体的特异性相互作用在介导HCV感染中发挥重要作用。 HCV 病毒粒子与脂蛋白的组装代表了一个新概念，值得进行探索性研究，并有望发现新型抗病毒药物。该应用的总体目标是确定含有 HCV RNA 的颗粒的特性和生化组成，并确定脂蛋白在 HCV 组装和感染中的作用。我们的具体目标是： 1) 使用结构、细胞生物学、生化、免疫学和蛋白质组学方法确定含 HCV RNA 颗粒的性质和生化组成以及 HCV 感染性的结构决定因素； 2) 通过改变稳定的HCV产生细胞中的脂蛋白产生水平以及使用针对特定载脂蛋白的抗体来定义脂蛋白在HCV病毒粒子产生和感染中的作用。脂蛋白的水平要么被载脂蛋白表达载体和化学诱导剂上调，要么被特定的siRNA和小分子抑制剂下调。此外，我们将确定人脂蛋白抑制 HCV 感染的潜在机制。这些研究的结果不仅将确定丙型肝炎病毒感染性的分子基础，还将为抗病毒干预提供新的靶点。此外，从我们的研究中获得的信息将为彻底了解 HCV 病毒粒子组装和感染的分子机制奠定基础。丙型肝炎病毒 (HCV) 感染构成了一个重大的全球健康问题，感染了美国约 400 万人和全球 1.7 亿人。该应用旨在确定 HCV 颗粒的特性和生化组成，并确定脂蛋白在 HCV 产生和感染中的作用。这些研究的结果将为 HCV 感染的抗病毒干预提供新的靶点和疗法。

项目成果

FGI-104: a broad-spectrum small molecule inhibitor of viral infection.

FGI-104：一种广谱病毒感染小分子抑制剂。

• 发表时间: 2009
• 期刊: American journal of translational research
• 影响因子: 2.2
• 作者: Kinch,MichaelS;Yunus,AbdulS;Lear,Calli;Mao,Hanwen;Chen,Hanson;Fesseha,Zena;Luo,Guangxiang;Nelson,EricA;Li,Limin;Huang,Zhuhui;Murray,Michael;Ellis,WilliamY;Hensley,Lisa;Christopher-Hennings,Jane;Olinger,GeneG;Goldblatt,M
• 通讯作者: Goldblatt,M