Impaired T cell function by HCV core

描述(申请人提供)：人类感染丙型肝炎病毒(丙型肝炎病毒)几乎总是与病毒持久性和慢性肝炎有关。慢性丙型肝炎是肝细胞癌发生的主要危险因素。丙型肝炎病毒持续感染的高发生率表明，这种病毒已经进化出一种或多种机制来逃避并可能抑制T淋巴细胞的反应。为了了解丙型肝炎病毒持续存在的机制(S)，我们将丙型肝炎病毒核心蛋白确定为能够抑制宿主免疫反应的免疫调节分子。 为了研究丙型肝炎病毒核心免疫抑制的分子基础，我们以编码补体C1q受体的基因gC1qR为宿主靶点，通过酵母双杂交结合丙型肝炎病毒核心蛋白，初步尝试寻找与核心蛋白结合的宿主蛋白(S)。已经获得的证据表明，这种联系是高度具体的。C1q是gC1qR的一个配体，参与感染的早期防御和获得性免疫的调节。和C1q一样，丙型肝炎病毒核心蛋白可以抑制人类T淋巴细胞的增殖反应。这些观察结果导致一种假设，即丙型肝炎病毒核心/gC1qR介导的T细胞功能抑制可能在丙型肝炎持续感染的建立中起关键作用。 本研究旨在探讨丙型肝炎病毒核心蛋白介导的T细胞功能抑制的潜在机制，并分析丙型肝炎病毒核心蛋白与gC1qR相互作用的结构基础。首先，我们将阐明丙型肝炎病毒核心蛋白抑制T淋巴细胞增殖反应的机制。其次，我们将进一步定义和表征丙型肝炎病毒核心蛋白与gC1qR之间的分子相互作用。最后，我们将表征来自急性和持续性感染的核心蛋白对T细胞功能的抑制。这些研究将有助于了解丙型肝炎病毒持续存在的机制。此外，它们还将为合理设计疫苗和新型治疗药物以阻断丙型肝炎病毒核心/gC1qR抑制T细胞功能的作用提供依据。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence and chronic hepatitis. Chronic hepatitis C is a major risk factor for the development of hepatocellular carcinoma. The high incidence of HCV persistence suggests that this virus has evolved one or more mechanisms to evade and possibly suppress T lymphocyte responsiveness. To understand the mechanism(s) involved in the establishment of HCV persistence, we have identified HCV core protein as an immunomodulatory molecule capable of suppressing host immune response. To investigate a molecular basis of HCV core-mediated immune suppression, we identified a gene encoding the C1q complement receptor, gC1qR as a host target, which binds HCV core protein by the yeast two hybrid in our initial attempt to search for a host protein(s) capable of association with HCV core. Evidence has been obtained that this association is highly specific. C1q is a ligand of gC1qR and is involved in the early defense against infection and regulation of adaptive immunity. Like C1q, HCV core can inhibit the human T lymphocyte proliferative response. These observations lead to a hypothesis that the HCV core/gC1qR-mediated inhibition of T cell function may play a critical role in the establishment of HCV persistent infection. This proposal is to investigate the underlying mechanism for HCV core-mediated suppression of T cell function and analyze a structural basis for HCV core and gC1qR interaction. First, we will elucidate the mechanism involved in the inhibition of T lymphocyte proliferative response by HCV core. Second, we will further define and characterize the molecular interaction between HCV core protein and gC1qR. Lastly, we will characterize the inhibition of T cell function by core proteins from acute and persistent infection. The proposed studies will help to understand the mechanism for the establishment of HCV persistence. In addition, they will provide a basis for the rational design of vaccines and novel therapeutic agents to block the action of HCV core/gC1qR on suppression of T cell function.