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

丙型肝炎病毒在人类中的感染几乎总是与病毒持续存在有关，病毒持续存在导致肝硬变和肝细胞癌的发生。在慢性丙型肝炎患者中，包括产生干扰素-g在内的细胞免疫反应严重受损。此外，丙型肝炎病毒诱导的免疫抑制与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。目的是了解丙型肝炎病毒感染急性期的宿主-病毒相互作用。为了了解丙型肝炎病毒逃避免疫的机制(S)，并设计治疗和改进免疫的策略，我们确定丙型肝炎病毒核心蛋白是一种免疫调节分子，可以抑制T细胞功能。此外，我们成功地证明了丙型肝炎病毒核心与补体受体(GC1qR)之间的一种新的相互作用，从而导致T细胞功能的抑制。C1q是gC1qR的配体，在先天免疫和获得性免疫调节中发挥重要作用。丙型肝炎病毒核心处理的CD4+T细胞 能够抑制CD8+T细胞。有趣的是，细胞外核心蛋白与T细胞上gC1qR的结合诱导了SHP-1的募集和SOCS1mRNA的表达。基于这些发现，我们推测，丙型肝炎病毒核心诱导的T细胞功能抑制可能在持续感染的建立中起作用。在这项建议中，我们将首先检查丙型肝炎病毒核心处理的CD4+T细胞抑制丙型肝炎病毒特异性CD8+T细胞的能力。第二，我们将表征SHP-1和SOCS1在核心处理的CD4+T细胞的T细胞抑制功能中的作用。第三，我们将确定gC1qR的表达水平和核心诱导的CD4+T细胞失调。这些研究将有助于阐明丙型肝炎病毒核心蛋白诱导免疫抑制的机制。此外，它们还将为合理设计新型治疗药物以阻断丙型肝炎病毒诱导的免疫抑制作用提供依据。

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.