Role of HCV in aberrant APC activation/function

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)在人类中的感染几乎总是与病毒持续导致慢性肝炎有关，而慢性肝炎又使感染者容易患上肝硬化和肝细胞癌。CD8+T细胞在控制丙型肝炎病毒感染中起着关键作用，但在慢性丙型肝炎患者中观察到严重的CD4+和CD8+T细胞功能障碍。这提示丙型肝炎病毒可能利用机制(S)来逃避或可能抑制宿主T细胞反应，尽管分子细节仍然难以捉摸。在探索可能的逃避机制(S)中，我们发现丙型肝炎病毒感染的肝细胞与巨噬细胞(M？)而先天免疫系统的树突状细胞(DC)抑制了它们产生促炎细胞因子的能力。此外，丙型肝炎病毒感染的肝细胞释放的可溶性因子(S)或分泌的核心蛋白通过激活STAT3转录因子改变APC的分化和功能，这是促进髓系抑制细胞(MDSCs)诱导和扩增的关键事件。有趣的是，暴露在丙型肝炎病毒中的APC表现出MDSC表型，并下调了HLA-DR的表达，并能够抑制干扰素？APC-T细胞共培养时CD+4+和CD8+T细胞的产生。基于这些发现，我们假设丙型肝炎病毒通过激活STAT3促进MDSCs的诱导/扩张，而这些调节的APC反过来抑制T细胞反应。首先，我们将表征丙型肝炎病毒诱导的STAT3激活在改变APC分化和功能中的作用。其次，我们将确定丙型肝炎病毒介导的APC功能障碍对受损的T细胞反应的影响。最后，我们将探讨丙型肝炎病毒诱导的抗原前体细胞功能障碍导致T细胞反应受损的机制(S)和潜在的治疗干预。本申请中提出的工作将阐明丙型肝炎病毒逃避宿主天然免疫，导致慢性病毒感染及其危及生命的并发症的机制。我们相信，这些研究结果将为绕过丙型肝炎病毒免疫抑制作用的人类抗丙型肝炎病毒感染疫苗和新疗法的合理设计提供依据。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence leading to chronic hepatitis, which in turn predisposes the infected individual to cirrhosis and hepatocellular carcinoma. CD8+ T-cells play a pivotal role in controlling HCV infection; however, severe CD4+ and CD8+ T-cell dysfunction has been observed in chronic HCV patients. This suggests that HCV may employ mechanism(s) to evade or possibly suppress the host T-cell response, although the molecular details have remained elusive. In exploring the possible evasion mechanism(s), we discovered that interaction of HCV-infected hepatocytes with macrophages (M?) and dendritic cells (DCs) of the innate immune system inhibited their ability to produce proinflammatory cytokines. Moreover, the soluble factor(s) released from HCV-infected hepatocytes or the secreted core protein altered APC differentiation and function by the activation of STAT3 transcription factor, which is a crucial event in promoting the induction and expansion of myeloid-derived suppressor cells (MDSCs). Intriguingly, APCs exposed to HCV exhibit the MDSC phenotype with downregulation of HLA-DR and are able to inhibit IFN-?? production by both CD+4+and CD8+ T-cells upon APC-T cell co-culture. Based on these findings, we hypothesize that HCV promotes the induction/expansion of MDSCs via STAT3 activation and that these regulatory APCs in turn suppress T-cell responses. First, we will characterize the role of HCV- induced STAT3 activation in altering APC differentiation and function. Second, we will determine the impact of HCV-mediated APC dysfunction on impairing T cell responses. Lastly, we will explore the mechanism(s) of impairment of T cell responses via HCV-induced APC dysfunction and potential therapeutic intervention. The work proposed in this application will elucidate the mechanism by which HCV evades host innate immunity, resulting in chronic viral infection and its life-threatening complications. We believe that results of these studies will provide a basis fr the rational design of vaccines and novel therapeutics against HCV infection in humans by bypassing the immunosuppressive effect of HCV.