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Hepacivirus control by T cells and broadly active antibodies

T 细胞和广泛活性抗体控制肝炎病毒

基本信息

批准号：
9294938
负责人：
ROBERT H MEALEY
金额：
$ 22.8万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294938
关键词：
Adoptive Transfer Adult Affect Alcohol or Other Drugs use Animal Model Animal Testing Alternatives Antibodies Antibody Response Antiviral Agents B-Lymphocytes Binding Biological Models CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD81 gene CD8B1 gene Cell Line Cessation of life Chronic Hepatitis C Cirrhosis Data Defect Developed Countries Developing Countries Epitopes Equus caballus Genome Genomics Glycoproteins Goals HCV Animal Models HCV screening Hepacivirus Hepatitis C Hepatitis C Vaccine Hepatocellular Damage Human Immune Immune response Immunity Infection Injecting drug user Interferon Type II Intravenous Kinetics Memory Methods Pan Genus Phase Phylogenetic Analysis Play Population Prevalence Prevention Primary carcinoma of the liver cells Proteins RNA Research Risk Role Route Severe Combined Immunodeficiency T memory cell T-Lymphocyte Testing Vaccine Design Vaccines Viral Virus Virus Replication cost cost effective cytotoxic experimental study injection drug use memory CD4 T lymphocyte neutralizing antibody novel protective effect response transmission process

项目摘要

Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma worldwide, with an estimated 185 million people infected and over 350,000 deaths a year. In developed countries, injection drug use is the predominant route of transmission and accounts for over two thirds of the HCV infections in the U.S., with up to 80% of injection drug users infected with HCV. Although new direct acting antiviral drugs will play an important role in controlling HCV, treatment is not likely to reduce global prevalence due to the high cost and because most people are subclinically infected and will not seek treatment. A protective vaccine would be much more cost-effective, but the correlates of protective immunity are not completely understood. Importantly, HCV only infects humans and chimpanzees, and because research on chimpanzees has been phased out, mechanisms of protective immunity must be rigorously dissected in an alternative animal model. Recently, a novel nonprimate hepacivirus has been described in horses. This equine hepacivirus (EHCV) is hepatotropic and is the closest known phylogenetic relative to HCV. The overall goal of the proposed studies is to delineate the protective roles of viral-specific memory T cells and antibodies against hepaciviral infection. The hypothesis to be tested is that horses that resolve EHCV infection mount broadly active memory T cell and/or antibody responses that are sufficient to control homologous and heterologous EHCV replication. We will use our established methods to first identify EHCV proteins containing conserved epitopes recognized by memory T cells from horses that have spontaneously resolved primary EHCV infection. Memory CD4+ T cell lines with high EHCV-specific proliferative responses will be expanded in culture, as will EHCV-specific IFNγ producing memory CD8+ T cell lines with cytotoxic activity. These T cells will then be transferred into MHC-matched horses with severe combined immunodeficiency (SCID) and protective effects against a mixed EHCV challenge determined. We will then similarly determine if antibodies that broadly inhibit EHCV E2 glycoprotein binding to equine CD81 are protective against EHCV challenge. These proposed studies will definitively demonstrate whether or not virus-specific T cells and/or antibodies can independently control EHCV infection and will have critical implications for HCV vaccine design, where experiments of this type are not possible.

丙型肝炎病毒（HCV）是全世界肝硬化和肝细胞癌的主要原因，估计每年有1.85亿人感染，超过35万人死亡。在发达国家，注射毒品使用是主要的传播途径，占美国HCV感染的三分之二以上，高达80%的注射吸毒者感染了HCV。虽然新的直接作用的抗病毒药物将发挥作用，尽管治疗在控制HCV方面发挥着重要作用，但由于成本高，因为大多数人是亚临床感染，不会寻求治疗。一种保护性疫苗更具成本效益，但保护性免疫的相关性尚未完全了解。重要的是，HCV 只感染人类和黑猩猩，因为对黑猩猩的研究已经被淘汰，保护性免疫的机制必须在另一种动物模型中严格剖析。近日一已经在马中描述了新的非灵长类肝炎病毒。这种马肝炎病毒（EHCV）是嗜肝的并且是已知相对于HCV最接近的系统发育。这项研究的总体目标是阐明病毒特异性记忆T细胞的保护作用。细胞和抗肝炎病毒感染的抗体。待检验的假设是，感染引起广泛活性记忆T细胞和/或抗体应答，其足以控制同源和异源EHCV复制。我们将使用我们建立的方法首先鉴定EHCV蛋白含有马的记忆T细胞识别的保守表位，原发性EHCV感染具有高EHCV特异性增殖反应的记忆性CD4 + T细胞系将被用于治疗EHCV。在培养物中扩增，EHCV特异性IFN γ产生记忆性CD8 + T细胞系具有细胞毒活性。然后这些T细胞将被转移到MHC匹配的患有严重联合免疫缺陷（SCID）的马匹中并确定对混合EHCV攻击的保护作用。然后我们将类似地确定抗体是否广泛抑制EHCV E2糖蛋白与马CD 81结合的抗体对EHCV攻击具有保护作用。这些拟议的研究将明确证明病毒特异性T细胞和/或抗体可以独立地控制EHCV感染并且将对HCV疫苗设计具有重要意义，这类实验是不可能的。