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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：
9012008
负责人：
Matthew J Evans
金额：
$ 26.36万
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/9012008
关键词：
Animal Model Animal Testing 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 Health 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 Genes 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 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.