Hepatic tolerance in chronic equine hepacivirus infection

丙型肝炎病毒（HCV）感染是全世界人类肝移植最常见的医学指征。该病毒显示出对宿主物种的狭窄偏好，自然只感染人类，尽管黑猩猩可能在实验中被感染。有限的宿主范围阻碍了强大的免疫动物模型的发展，这反过来又阻碍了病毒发病机理和免疫控制的机制分析。与动物肝炎病毒（HV）关系最密切的是马肝炎病毒（EqHV）。EqHV与HCV类似，可引起急性和慢性感染，病毒血症持续数月至数年。与丙型肝炎病毒一样，有效免疫反应的主要决定因素尚未确定。到目前为止，还没有预防或治疗的方法。因此，迫切需要开发一种新的通用方法，以创新和合理地设计疫苗和治疗措施。在这个项目中，我们的目的是评估治疗性疫苗对慢性感染马的EqHV感染的免疫学影响。这些发现将增强我们对肝炎病毒特异性疫苗接种和感染的免疫活性宿主免疫反应的认识。除了深入了解马的免疫反应外，该系统还具有作为人类HCV潜在治疗策略的替代模型的巨大潜力。我们将生成四种不同的重组MVA病毒，表达EqHV- e1 /E2、EqHV- ns3、EqHV- ns5b抗原，并测试基于MVA的疫苗接种是否能安全地诱导载体特异性和EqHV特异性t细胞反应，并导致感染EqHV的马的病毒载量降低。

Hepatitis C virus (HCV) infection is the most frequent medical indication for liver transplantation in humans worldwide. The virus displays a narrow host species tropism and naturally only infects humans, although chimpanzees may be infected experimentally. The restricted host range has hampered the development of a robust immunocompetent animal model, which in turn has hindered the mechanistic analysis of virus pathogenesis and immune control. The most closely related animal hepacivirus (HV) is found in horses, the equine hepacivirus (EqHV). EqHV, similar to HCV, can cause acute and chronic infections, with viremia lasting for months to years. As in HCV, the major determinants of an effective immune response have not been identified. So far there are no preventive or therapeutic approaches available. Thus, the development of a novel general approach for innovative and rational design of vaccines and therapeutic measures is urgently needed. In this project we aim to evaluate the immunological impact of therapeutic vaccination against EqHV infection in chronically infected horses. These findings will enhance our knowledge of an immunocompetent host immune response to hepacivirus specific vaccination and infection. In addition to providing insights into the horse’s immune response, the system holds great potential as a surrogate model for a potential therapeutic strategy against HCV in humans. We will generate four different recombinant MVA viruses expressing the EqHV-E1/E2, EqHV-NS3, EqHV-NS5B antigens and test whether MVA-based vaccination can safely induce vector specific and EqHV-specific T-cell responses and lead to a reduction in viral load in EqHV infected horses.