Characterization and Consequences of HCV Interaction with Host Lipoproteins

HCV 与宿主脂蛋白相互作用的特征和后果

• 批准号: 8001512
• 负责人: Margaret Adele Scull
• 金额: $ 4.56万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001512
• 关键词: Address; Binding; Biochemical; Biological Assay; Cataloging; Catalogs; Cells; Complement; Complement Activation; Complex; Data; Development; Glycoproteins; Hepatitis C Prevalence; Hepatitis C virus; Heterogeneity; High Density Lipoproteins; Immune system; Individual; Infection; Kinetics; Licensing; Life Cycle Stages; Link; Lipids; Lipoproteins; Liver Cirrhosis; Low-Density Lipoproteins; Mediating; Membrane Glycoproteins; Molecular; Mutagenesis; Nature; Pathway interactions; Population Heterogeneity; Predisposition; Primary carcinoma of the liver cells; Proteins; Proteomics; Role; Vaccines; Viral; Virion; Virus; Virus Diseases; density; design; effective therapy; insight; neutralizing antibody; population based; public health relevance; virus pathogenesis

DESCRIPTION (provided by applicant): Over 170 million people world-wide are infected with hepatitis C virus (HCV), a major cause of liver cirrhosis and hepatocellular carcinoma. Despite the global prevalence of HCV, little is known about how this virus interacts with the host and evades the immune system to establish persistent infection. HCV circulates in infected individuals as a heterogeneous population based on buoyant density and this heterogeneity is due in part to virus association with lipoproteins - including very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins. HCV association with lipoproteins initiates during virus particle assembly, and release of progeny HCV is closely linked to the VLDL secretory pathway. Entry into susceptible cells is also facilitated by interaction with lipoproteins, specifically HDL, which promotes rapid kinetics of entry thought to facilitate escape from neutralizing antibodies. Together, these data support the interaction between HCV and lipoproteins and underscore their role in HCV pathogenesis, however, the precise nature of how these lipoproteins interact with HCV is unknown and the full consequences of their interaction not fully explored. Our overall hypothesis is that HCV virion association with, or incorporation of, host proteins and lipids reduces virus susceptibility to neutralization. Previous studies indicate that lipoprotein interaction is mediated by the HCV surface glycoproteins, E1 and E2. In Specific Aim 1, we will define the specific molecular requirements for lipoprotein (specifically HDL)-HCV interaction using both biochemical assays to dissect the HDL complex and a glycoprotein mutagenesis strategy to identify critical viral residues for binding. Independent of viral infection, lipoproteins have been shown to have immunoregulatory activities, and HDL has specifically been shown to modulate complement activation. Thus, in Specific Aim 2 we will investigate the impact of HCV association with HDL on virus susceptibility to complement-mediated virolysis. Our final Specific Aim is to perform complete proteomic and lipidomic analyses on purified HCV. These data will not only further elucidate the lipoprotein-virus interaction, but will also enable us to catalog the cellular components of the virus particle. Such analyses will provide valuable insight into the composition of the HCV particle and its life cycle. PUBLIC HEALTH RELEVANCE: Over 170 million people world-wide are infected with HCV, a major cause of liver cirrhosis and hepatocellular carcinoma. No licensed vaccine or universally effective therapy is available to date and development of better treatment options will require further understanding of how HCV interacts with the host to establish persistent infection. To address this, the studies outlined in this application are designed to define the specific interaction between HCV and host lipoproteins and investigate the impact of this interaction on viral evasion of the host immune system.

描述（由申请人提供）：全球超过1.7亿人感染了丙型肝炎病毒（HCV），这是肝硬化和肝细胞癌的主要原因。尽管HCV的全球患病率是该病毒如何与宿主相互作用并逃避免疫系统以建立持续感染的情况，但知之甚少。 HCV基于浮力密度将受感染个体作为异质种群循环，并且这种异质性部分归因于病毒与脂蛋白的关联 - 包括非常低的密度（VLDL），低密度（LDL）和高密度（HDL）脂蛋白。 HCV与脂蛋白在病毒颗粒组装过程中的启动，后代HCV的释放与VLDL分泌途径密切相关。通过与脂蛋白（特别是HDL）相互作用，还可以促进进入易感细胞的进入，该脂蛋白具有HDL，该动力学促进了被认为可以促进中和抗体逃脱的进入动力学。这些数据共同支持HCV和脂蛋白之间的相互作用，并强调它们在HCV发病机理中的作用，但是，这些脂蛋白与HCV相互作用的确切性质尚不清楚，并且相互作用的全部后果未得到充分探索。我们的总体假设是，HCV病毒素与宿主蛋白和脂质的结合或掺入降低了病毒对中和的敏感性。先前的研究表明，脂蛋白相互作用是由HCV表面糖蛋白E1和E2介导的。在特定的目标1中，我们将使用两种生化测定方法来定义脂蛋白（特异性HDL）-HCV相互作用的特定分子需求，以剖析HDL复合物和糖蛋白诱变策略，以鉴定关键的病毒残基。与病毒感染无关，脂蛋白已被证明具有免疫调节活性，并且HDL已被特异性证明可以调节补体激活。因此，在特定的目标2中，我们将研究HCV与HDL的影响对病毒易感性介导的病毒式流溶性的影响。我们的最终特定目的是对纯化的HCV进行完整的蛋白质组学和脂质分析分析。这些数据不仅将进一步阐明脂蛋白 - 病毒相互作用，而且还将使我们能够对病毒颗粒的细胞成分进行分类。这种分析将为HCV粒子及其生命周期的组成提供宝贵的见解。 公共卫生相关性：全球超过1.7亿人感染了HCV，这是肝硬化和肝细胞癌癌的主要原因。迄今为止，没有许可的疫苗或普遍有效的疗法可以使用更好的治疗选择，需要进一步了解HCV与宿主的相互作用以建立持久感染。为了解决这个问题，本应用中概述的研究旨在定义HCV和宿主脂蛋白之间的特定相互作用，并研究这种相互作用对宿主免疫系统病毒逃避的影响。