Genetic viral and host adaptations to breach species barriers of HCV

遗传病毒和宿主适应突破丙型肝炎病毒的物种障碍

基本信息

批准号：
8562610
负责人：
Alexander Ploss
金额：
$ 37.84万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8562610
关键词：
Address Animal Model Antiviral Agents Antiviral Therapy Behavior CD81 gene Cell Culture Techniques Cells Chronic Chronic Hepatitis C Cirrhosis Cyclophilin A Data Development Epidemic Evolution Family Fibrosis Flaviviridae Future Genes Genetic Growth HCV Vaccine Hepatitis C Hepatitis C virus Hepatocyte Human Immune response Immunity Immunocompetent Immunocompromised Host In Vitro Inbred Mouse Inbred Strains Mice Individual Infection Lead Life Cycle Stages Light Liver Liver diseases Measurable Mus Pan Genus Pathogenesis Pathology Patients Peptide Hydrolases Primary carcinoma of the liver cells RNA Viruses RNA replication Reporter Research Risk Speed Testing Transgenic Mice Transgenic Organisms Tropism United States National Institutes of Health Vaccines Variant Viral Viremia Virus Virus Replication base cost cost effective drug candidate effective therapy in vivo longitudinal analysis mouse model occludin particle pre-clinical prophylactic public health relevance therapeutic vaccine uptake vaccine candidate viral RNA virus genetics

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C remains a global epidemic. At least 130 million individuals suffer from chronic hepatitis C, which is caused by hepatitis C virus (HCV) - a positive sense, single-stranded RNA virus of the Flaviviridae family. HCV has a high propensity for establishing chronic infection. If untreated chronic HCV carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Antiviral treatment is only partially effective, costly and often poorly tolerated. A prophylactic or therapeutic vaccine for HCV does not exist. Development of more effective therapies and vaccines has been hampered by the lack of a suitable small animal model.! Building on our previous observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive for HCV entry in vitro, we attempted murine humanization via a genetic approach. We demonstrated that expression of the two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We provide comprehensive preliminary data demonstrating that a combination of innate and adaptive immune responses restricts persistent HCV replication in these mice. We demonstrate that blunting antiviral immunity in mice expressing human CD81 and OCLN results in low level, viremia over several weeks. This observation provides critical evidence for the feasibility of adapting HCV to replicate efficientlyin conditioned inbred mouse strain. We now propose to systematically overcome additional blocks to interspecies growth of the HCV by exploiting HCV's remarkable genetic plasticity. Our studies will ultimately lead to a fully immunocompetent mouse model for HCV infection, which we will use to study HCV-associated liver disease. An inbred mouse model that supports the entire HCV life-cycle opens unprecedented opportunities to genetically dissect HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug and vaccine candidates. !

描述（由申请人提供）：丙型肝炎仍然是全球流行病。至少有1.3亿人患有慢性丙型肝炎，这是由丙型肝炎病毒（HCV）引起的-A flaviviridae家族的积极意义，单链的RNA病毒。 HCV具有建立慢性感染的高倾向。如果未经治疗的慢性HCV载体可以发展出严重的肝病，包括纤维化，肝硬化和肝细胞癌（HCC）。抗病毒治疗仅部分有效，昂贵且耐受性不佳。不存在用于HCV的预防性或治疗性疫苗。缺乏合适的小动物模型，阻碍了更有效的疗法和疫苗的开发。基于我们以前的观察，CD81和Occludin（OCLN）构成了使小鼠细胞在体外允许进入HCV所需的最小人为因素，我们尝试通过遗传方法进行鼠类人性化。我们证明了两个人类基因的表达足以使HCV感染完全免疫能力的近交小鼠。我们提供了全面的初步数据，表明先天和适应性免疫反应的组合限制了这些小鼠的持续性HCV复制。我们证明，表达人CD81和OCLN的小鼠的抗病毒免疫会导致低水平，病毒血症在几周内。该观察结果为适应HCV复制效应的近交小鼠菌株的可行性提供了关键的证据。现在，我们建议通过利用HCV出色的遗传可塑性来系统地克服其他块，以使HCV的种间增长。我们的研究最终将导致用于HCV感染的完全免疫能力的小鼠模型，我们将用于研究与HCV相关的肝病。一种支持整个HCV生命周期的近交小鼠模型为体内遗传解剖HCV感染开辟了前所未有的机会，并为测试和优先考虑药物和疫苗候选者提供了重要的临床前平台。呢