IMMUNOGENETHERAPY OF CHRONIC HCV CARRIER CHIMPANZEES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在急性自限性丙型肝炎患者中，通常观察到强烈的hcv特异性T细胞反应。相反，在持续感染的患者中，T细胞反应较弱且狭窄。有研究提出，慢性感染个体增强和/或从头诱导HCV特异性细胞免疫反应将诱导HCV清除和恢复。这一假设只能在黑猩猩身上得到验证，黑猩猩是唯一易受HCV感染的动物。我们建议用表达HCV NS3、NS4和NS5B的重组载体接种2只HCV携带者黑猩猩，以诱导HCV特异性T细胞反应，并评估这些HCV特异性T细胞是否可以通过减少或消除病毒血症和/或控制HCV抗原表达来影响HCV携带者状态。该疫苗有两种成分，重组丙型肝炎病毒痘病毒（MVA-HCV）和重组丙型肝炎病毒腺病毒（Ad-HCV），并将在初始强化方案中应用。该疫苗表达3种HCV抗原，即HCV NS3、NS4和NS5B。腺病毒和MVA都是t细胞免疫的强诱导剂。一只携带丙肝病毒的黑猩猩将被模拟接种不表达丙肝病毒抗原的载体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vigorous HCV-specific T cell responses are typically observed in patients who recover spontaneously from acute, self-limited hepatitis C. In contrast, T cell responses are weak and narrowly focused in persistently infected patients. It has been proposed that enhancement and/or de novo induction of HCV-specific cellular immune responses in chronically infected individuals will induce HCV clearance and recovery. This hypothesis can only be tested in chimpanzees, the only animals susceptible to HCV infection. We propose to vaccinate 2 HCV carrier chimpanzees with recombinant vectors expressing HCV NS3, NS4 and NS5B to induce HCV-specific T cell responses and to evaluate whether these HCV-specific T cells can impact on HCV carrier state, by reducing or eliminating viremia and/or by controlling HCV antigen expression. The vaccine has 2 components, a recombinant HCV pox-virus (MVA-HCV) and a recombinant HCV adenovirus (Ad-HCV), and will be applied in a prime-boost regimen. The vaccine expresses 3 HCV antigens, namely HCV NS3, NS4 and NS5B. Both adenoviruses and MVA are known to be strong inducers of T-cell immunity. One HCV carrier chimpanzee will be mock vaccinated with vectors that do not express the HCV antigens.