Suppression of HCV-specific CD4+ T Cells by Core Protein

人类丙型肝炎病毒（HCV）感染几乎总是与病毒持续性相关，从而导致肝硬化和肝细胞癌的发展。在慢性HCV患者中，细胞免疫反应包括IFN-g的产生严重受损。此外，hcv诱导的免疫抑制与对细菌和其他肠道病毒感染的易感性增加有关。因此，丙型肝炎病毒很可能进化出一种策略，通过编码能够抑制宿主免疫反应的基因产物来避免宿主免疫监视。目的是了解HCV感染急性期宿主-病毒的相互作用。为了了解丙型肝炎病毒的免疫逃避机制，设计治疗和改进免疫的策略，我们确定了丙型肝炎病毒核心蛋白作为抑制T细胞功能的免疫调节分子。此外，我们成功地证明了HCV核心和补体受体（gC1qR）之间的一种新的相互作用，导致T细胞功能的抑制。C1q是gC1qR的配体，在先天免疫和适应性免疫调控中起关键作用。HCV核心处理的CD4+ T细胞

Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence, which leads to the development of liver cirrhosis and hepatocellular carcinoma. In chronic HCV patients, cellular immune responses including the production of IFN-g are severely impaired. In addition, HCV-induced immune suppression is associated with increased susceptibility to bacteria and other enteric viral infections. Thus, HCV most likely evolved a strategy to avoid host immune surveillance by encoding gene products, which are capable of dampening host immune responses. The goal is to understand host-virus interaction during the acute phase of HCV infection. To understand the mechanism(s) of immune evasion by HCV and to design strategies for therapeutics and improved immunization, we identified the HCV core protein as an immunomodulatory molecule to inhibit T cell function. In addition, we successfully demonstrated a novel interaction between HCV core and complement receptor (gC1qR) leading to inhibition of T cell function. C1q is a ligand for gC1qR and plays a critical role in innate immunity, as well as, regulation of adaptive immunity. HCV core-treated CD4+ T cells are able to suppress CD8+ T cells. Intriguingly, the binding of extracellular core protein to gC1qR on T cells induced SHP-1 recruitment and SOCS1 mRNA expression. Based on these findings, we hypothesize that HCV core-induced suppression of T cell function may play a role in the establishment of persistent infection. In this proposal, we will first examine the ability of HCV core-treated CD4+ T cells to suppress HCV-specific CD8+ T cells. Second, we will characterize the role of SHP-1 and SOCS1 in the T cell inhibitory function of core-treated CD4+ T cells. Third, we will determine the gC1qR expression level and core-induced CD4+ T cell dysregulation. The studies proposed here will help to elucidate the mechanisms of HCV core-induced immunosuppression. In addition, they will provide a basis for the rational design of novel therapeutic agents to block the action of HCV-induced immunosuppression.