Impaired T cell function by HCV core

描述（由申请人提供）：人类丙型肝炎病毒（HCV）感染几乎总是与病毒持续存在和慢性肝炎相关。慢性丙型肝炎是肝细胞癌发展的主要危险因素。HCV持续性的高发病率表明，这种病毒已经进化出一种或多种机制，以逃避和可能抑制T淋巴细胞的反应。为了了解HCV持续存在的机制，我们已经确定HCV核心蛋白是一种能够抑制宿主免疫反应的免疫调节分子。 为了研究HCV核心介导的免疫抑制的分子基础，我们鉴定了编码C1 q补体受体的基因gC 1 qR作为宿主靶标，其通过酵母双杂交结合HCV核心蛋白，以寻找能够与HCV核心结合的宿主蛋白。已经获得的证据表明，这种关联是高度特异性的。C1 q是gC 1 qR的一种配体，参与感染的早期防御和适应性免疫的调节。与C1 q一样，HCV core也能抑制人T淋巴细胞增殖反应。这些观察结果导致了一个假设，即HCV核心/gC 1 qR介导的T细胞功能抑制可能在HCV持续感染的建立中起关键作用。 本研究旨在探讨HCV核心介导的T细胞功能抑制的潜在机制，并分析HCV核心和gC 1 qR相互作用的结构基础。首先，我们将阐明HCV核心抑制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HCV核心蛋白和gC 1 qR之间的分子相互作用。最后，我们将描述急性和持续性感染的核心蛋白对T细胞功能的抑制作用。拟议的研究将有助于了解HCV持续存在的机制。此外，它们将为合理设计疫苗和新型治疗药物以阻断HCV core/gC 1 qR对T细胞功能的抑制作用提供基础。

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.