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：
9169140
负责人：
ROBERT H MEALEY
金额：
$ 18.99万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9169140
关键词：
Accounting Adult Affect Alcohol or Other Drugs use Animal Hepatitis Animal Model Antibodies Antibody Response Antiviral Agents B-Lymphocytes Binding Biological Models CD4 Positive T Lymphocytes CD81 gene CD8B1 gene Cell Line Cessation of life Chronic Hepatitis C Cirrhosis Data Defect Developed Countries Epitopes Equus caballus Genome Genomics Glycoproteins Goals HCV screening Hepacivirus Hepatitis C Hepatitis C Vaccine Hepatitis C virus 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 cell response T memory cell T-Lymphocyte Testing Vaccine Design Vaccines Viral Virus Virus Replication cost cost effective cytotoxic injection drug use memory CD4 T lymphocyte neutralizing antibody novel protective effect research study 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，据估计，在发达国家，注射毒品每年有 1.85 亿人感染，超过 35 万人死亡。使用是主要的传播途径，占美国丙型肝炎病毒感染的三分之二以上，尽管新的直接作用抗病毒药物将发挥作用，但高达 80% 的注射吸毒者感染了 HCV。虽然治疗在控制 HCV 方面发挥着重要作用，但由于费用高且成本低，不太可能降低全球患病率因为大多数人都是亚临床感染，不会寻求治疗。保护性疫苗的作用就很大。更具成本效益，但保护性免疫的相关性尚未完全了解。只感染人类和黑猩猩，而且由于对黑猩猩的研究已被逐步淘汰，最近，必须在另一种动物模型中严格剖析保护性免疫机制。新型非灵长类肝炎病毒已在马中被描述。这种马肝炎病毒 (EHCV) 是嗜肝性的。是已知与 HCV 最接近的系统发育亲缘关系。拟议研究的总体目标是描述病毒特异性记忆 T 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马能够解决 EHCV 问题。感染引起广泛活跃的记忆T细胞和/或抗体反应，足以控制同源我们将使用我们已建立的方法首先鉴定 EHCV 蛋白。含有马记忆 T 细胞识别的保守表位，这些表位已自发解决具有高 EHCV 特异性增殖反应的记忆 CD4+ T 细胞系将是原发性 EHCV 感染。在培养物中扩增，产生具有细胞毒活性的 EHCV 特异性 IFNγ 记忆 CD8+ T 细胞系。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) 的马体内然后我们将类似地确定抗体是否对混合 EHCV 攻击具有保护作用。广泛抑制 EHCV E2 糖蛋白与马 CD81 的结合，可防止 EHCV 攻击。这些拟议的研究将明确证明病毒特异性 T 细胞和/或抗体可以独立控制 EHCV 感染，并对 HCV 疫苗设计产生重要影响，不可能进行此类实验的地方。