Host and viral determinants of hepatitis C virus macaque infection

丙型肝炎病毒猕猴感染的宿主和病毒决定因素

基本信息

批准号：
8914166
负责人：
Matthew J Evans
金额：
$ 23.51万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-10 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914166
关键词：
Animal Model Animal Use Alternatives Animals CD81 gene Cell Culture Techniques Cells Chimera organism Defect Detection Development Disease Enzymes Ethics Exhibits Figs - dietary Genetic Genotype Goals Grant HCV Animal Models HIV-1 Hepatic Hepatitis C Hepatitis C Antibodies Hepatitis C Vaccine Hepatitis C virus Hepatocyte Human Immunity Immunocompetent Infection Inflammation Lead Left Liver Liver diseases Macaca Macaca mulatta Macaca nemestrina Malignant neoplasm of liver Modeling Monitor Monkeys Mus Mutation North America Pan Genus Pathogenesis Patients Play Primary carcinoma of the liver cells Primates Process Proteins Reagent Research Research Personnel Risk Role Sampling Serum Structural Protein Supporting Cell Testing Time Tropism United States United States National Institutes of Health Vaccine Design Vaccines Variant Viral Virus Virus Receptors Virus Replication Work arm base clinically relevant combat fitness in vivo induced pluripotent stem cell insight liver injury mutant pathogen public health relevance research study screening tool vaccine evaluation viral RNA virus genetics virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The hepatitis C virus (HCV) is the leading cause of liver cancer in the Western Hemisphere. Over 170 million people are infected with this virus and consequently at increased risk of liver damage and cancer. Understanding how this virus induces liver disease and the development of a much-needed vaccine requires an immunocompetent HCV animal model. The dogma in the HCV field was that this virus only infects humans and chimpanzees. As a recent NIH moratorium on chimpanzee research has effectively prohibited use of these animals, an alternative immunocompetent HCV animal model is desperately needed. To explore if small primates can support HCV infection, we generated hepatocytes from pigtail macaque-(Macaca nemestrina, Mn) induced pluripotent stem cell-derived hepatic cells. Surprisingly, these cells supported detectable levels of infection with cell culture derive genotype 2a HCV. We found that inefficient function of the macaque version of the HCV receptor, CD81, limited HCV infection of these cells. A mutant genotype 2a virus that can use CD81 proteins from a wide range of species overcame this block and efficiently infected the macaque hepatocytes. We have recently made the startling discovery that both wild type and mutant versions of this virus could infect pigtail macaques in vivo, thus demonstrating for the first time that HCV can replicate in animals other than humans and chimpanzees. In this grant we propose experiments to further characterize macaque HCV infections. This will include determining if rhesus macaques, which are more readily available and a larger set of species-specific reagents than pigtail macaques are obtainable, can also be infected with genotype 2a HCV. We will also examine the viral determinants for HCV infection of macaques. We will explore mechanisms by which virus can adapt to more efficiently replicate in this host and determine if we are able to expand the range of viral isolates that can infect NHPs. Ultimately, our studies will provide the first immunocompetent tractable animal models that will establish new avenues to explore HCV replication and pathogenesis in vivo with the eventual goal of developing efficacious vaccine against this virus.

描述（由适用提供）：丙型肝炎病毒（HCV）是西半球肝癌的主要原因。超过1.7亿人感染了这种病毒，因此增加了肝脏损害和癌症的风险。了解该病毒如何诱导肝病和急需的疫苗的发展需要免疫能力的HCV动物模型。 HCV领域的教条是该病毒仅感染了人类和黑猩猩。由于最近对黑猩猩研究的NIH暂停已有效地禁止使用这些动物，因此迫切需要一种替代性的免疫能力HCV动物模型。为了探索小私人是否可以支持HCV感染，我们从紫尾猕猴（Macaca Nemestrina，MN）产生了肝细胞，诱导了多能干细胞衍生的肝细胞。令人惊讶的是，这些细胞支持可检测到的细胞感染水平培养得出基因型2a HCV。我们发现HCV受体CD81的猕猴版本的功能无效，有限的HCV感染。一种突变基因型2a病毒，可以使用来自广泛物种的CD81蛋白克服了该块并有效感染了猕猴的肝细胞。我们最近开始发现，该病毒的野生型和突变版本都可以在体内感染辫子猕猴，因此首次证明了HCV可以在人类和黑猩猩以外的动物中复制。在这笔赠款中，我们提出了实验，以进一步表征猕猴HCV感染。这将包括确定是否更容易获得的恒河猕猴，并且比尾巴猕猴更容易获得，并且还可以被基因型2A HCV感染。我们还将检查猕猴HCV感染的病毒决定剂。我们将探索病毒可以在此宿主中更有效复制的机制，并确定我们是否能够扩大可以感染NHP的病毒分离株的范围。最终，我们的研究将提供第一个免疫能力的拖延动物模型，该模型将建立新的途径，以探索体内HCV复制和发病机理，其事件目标是针对该病毒开发有效的疫苗。