Role of HCV* Hepatocyte in Regulation of Antiviral T cell Immunity

丙型肝炎病毒合作研究中心项目2有助于了解获得性免疫的调节 在急性丙型肝炎病毒感染过程中，感染丙型肝炎病毒的肝细胞与CD4T细胞相互作用。丙型肝炎病毒感染 在建立病毒持久性方面非常有效，导致肝脏发育 肝硬变和肝细胞癌。CDS T细胞参与控制丙型肝炎病毒感染；在慢性病 丙型肝炎患者，已观察到严重的CD4和CDS T细胞功能障碍。这表明丙型肝炎病毒可能 采用某种机制来抵消或可能抑制宿主T细胞的反应。的主要站点 病毒复制是在肝脏的肝细胞内进行的。在感染丙型肝炎期间，有增加的人口 肝窦中的CD4T细胞，允许与感染丙型肝炎病毒的肝细胞密切接触。要确定 丙型肝炎病毒感染的肝细胞与CD4T细胞的相互作用是否改变了CD4T细胞的辅助功能 塑造CDS T细胞效应抗病毒活性，我们对丙型肝炎病毒感染的肝细胞进行了共培养研究 与CD4T细胞有关。我们的初步研究表明，肝细胞表达完整的丙型肝炎病毒 蛋白质(即丙型肝炎病毒+肝细胞)上调PD-1阴性共刺激分子B7-H1的配体， 和转化生长因子-β的合成。此外，丙型肝炎病毒阳性的肝细胞能够损害CD4T细胞的功能，包括 抑制干扰素-g的产生。基于这些发现，我们假设丙型肝炎病毒+肝细胞介导 CD4T细胞功能抑制在抗病毒CDS T细胞效应器功能受损中起着关键作用。为了测试 这一假设，我们提出三个具体的施舍，我们将首先探讨丙型肝炎病毒+肝细胞介导的机制 抑制CD4T细胞反应。第二，我们将确定丙型肝炎病毒+肝细胞诱导的影响 CD4T细胞功能障碍对抗病毒CDS T细胞功能的调节作用。最后，我们将研究 急性丙型肝炎患者外周血中CD4T细胞分化状态及其与丙型肝炎病毒感染结局的关系 病人。这些研究的结果将为设计治疗策略提供有价值的见解 与丙型肝炎病毒感染有关。

The project 2 of HCV Cooperative Research Center alms to understand the regulation of adaptive Immunity via the Interaction of HCV-infected hepatocytes with CD4 T cells during acute HCV Infection. HCV Infection In humans is remarkably efficient In establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma. CDS T cells are Involved in controlling HCV Infection; but. In chronic HCV patients, severe CD4 and CDS T cell dysfunction has been observed. This suggests that HCV may employ some mechanism to counteract or possibly suppress the host T cell response. The primary site of viral replication is within hepatocytes in the liver. During HCV Infection, there is the increased population of CD4 T cells in the liver sinusoid, which allows close contact with HCV-infected hepatocytes. To determine whether the Interaction of HCV-infected hepatocytyes with CD4 T cells alters CD4 T cell helper function on shaping CDS T cell effector antiviral activity, we conducted co-culture studies of HCV-infected hepatocytes with CD4 T cells. Our preliminary studies, we demonstrated that hepatocytes expressing whole HCV proteins (I.e. HCV+ hepatocytes) upregulated the ligand of PD-1 negative costimulatory molecule, B7-H1, and TGF-b synthesis. In addition, HCV+ hepatocytes are capable of impairing CD4 T cell function including Inhibition of IFN-g production. Based on these findings, we hypothesize that HCV+ hepatocyte-mediated Inhibition of CD4 T cell function plays a pivotal role In Impairing antiviral CDS T cell effector function. To test this hypothesis, we propose three specific alms, we will first explore the mechanism for HCV+ hepatocyte mediated Inhibition of CD4 T cell responses. Second, we will determine the impact of HCV+ hepatocyte induced CD4 T cell dysfunction on regulating antiviral CDS T cell effector function. Lastly, we will examine the status of CD4 T cell differentiation and correlate it with the outcome of HCV infection during acute HCV patients. Results of these studies will provide valuable insight Into designing therapeutic strategies against to HCV Infection.