The Role of PD-1 and SOCS-1 in regulating T cell responses in HCV infection

描述（由申请人提供）：PD-1和SOCS-1在HCV感染中调节T细胞反应中的作用。本研究的总体目标是确定负调节因子，程序性细胞死亡-1 （PD-1）和细胞因子信号传导抑制因子-1 （SOCS-1）在慢性丙型肝炎病毒（HCV）感染期间调节T细胞反应中的作用。HCV在破坏人T细胞功能和建立持续感染方面表现突出，从而为研究病毒介导的T细胞功能障碍机制提供了一个很好的模型。我们最近的体外和离体研究表明，HCV核心蛋白可以通过与T淋巴细胞上的补体受体gC1qR相互作用来抑制T细胞反应。有趣的是，这种HCV核心/ gc1qr介导的T细胞功能障碍与PD-1和SOCS-1的诱导有关。此外，gC1qR和PD-1在慢性HCV感染个体的T细胞表面被发现过表达，尽管PD-1是否在病毒特异性T细胞上上调及其在调节T细胞受体（TCR）信号传导中与SOCS-1的关系尚不清楚。基于这些有趣的发现和新的研究表明PD-1和SOCS-1在T细胞激活过程中对TCR信号通路的负调控中起关键作用，我们假设PD-1和SOCS-1在HCV感染期间上调并导致TCR信号通路的破坏。作为检验这一假设的初步方法，我们将定量分析慢性HCV感染患者（治疗前后干扰素应答和无应答）的病毒特异性和总CD3+/CD4+或CD3+/CD8+ T细胞中PD-1和SOCS-1的动态表达，并将其水平与健康献血者进行比较。为了深入了解PD-1和SOCS-1调节T细胞反应的机制，我们将研究它们在hcv感染患者T细胞中TCR信号传导中的作用。此外，我们将剖析gC1qR、PD-1和SOCS-1在调节T细胞反应中的关系，这些T细胞反应对病毒清除至关重要。拟议的研究可能会提供病原体篡夺宿主机制以促进持久性的新机制，以及设计慢性病毒感染治疗和/或疫苗策略的基本原理。丙型肝炎病毒（HCV）是一个以慢性感染高发为特征的全球性健康问题，但这种病毒如何能够逃避人类免疫系统尚不清楚。在本研究中，我们将研究两种新的免疫反应调节剂，程序性死亡-1 （PD-1）和细胞因子信号传导抑制因子-1 （SOCS-1）在调节慢性HCV感染中受损的T细胞反应中的作用。这项研究可能揭示病毒逃避人类免疫监视而建立持续感染的基本机制。

DESCRIPTION (provided by applicant): The role of PD-1 and SOCS-1 in regulating T cell responses in HCV infection. The overall goal of this study is to determine the role of the negative modulators, programmed cell death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1), in regulation of T cell responses during chronic hepatitis C virus (HCV) infection. HCV is remarkable at disrupting human T cell function and establishing persistent infection, thus providing an excellent model to study the mechanisms of virus-mediated T cell dysfunction. Our recent studies, both in vitro and ex vivo, have shown that HCV core protein can inhibit T cell responses through its interaction with a complement receptor, gC1qR, on T lymphocytes. Interestingly, this HCV core/gC1qR-mediated T cell dysfunction is associated with induction of PD-1 and SOCS-1. Additionally, gC1qR and PD-1 are found over- expressed on the surface of T cells in individuals chronically infected with HCV, although whether PD- 1 is up-regulated on viral specific T cells and its relationship to SOCS-1 in regulating T cell receptor (TCR) signaling remains unknown. Based on these intriguing findings and novel studies showing that both PD-1 and SOCS-1 play pivotal roles in negative regulation of TCR signaling during T cell activation, we hypothesize that PD-1 and SOCS-1 are up-regulated during HCV infection and lead to disruption of TCR signaling. As an initial approach to test this hypothesis, we will quantitatively analyze the kinetic expression of PD-1 and SOCS-1 in viral specific as well as total CD3+/CD4+ or CD3+/CD8+ T cells from chronically HCV- infected patients (interferon responders and non-responders, before and after treatment), and compare their levels with those of healthy blood donors. To gain insight into the mechanism(s) by which PD-1 and SOCS-1 regulate T cell responses, we will examine their roles in TCR signaling in T cells from HCV-infected patients. We will moreover dissect the relationships between gC1qR, PD-1, and SOCS-1 in regulating T cell responses that are critical for viral clearance. The proposed studies would potentially provide a novel mechanism by which pathogens usurp the host machinery to facilitate persistence, as well as a rationale for designing therapeutics and/or vaccine strategies for chronic viral infections. Hepatitis C virus (HCV) is a global health problem characterized by a high incidence of chronic infection, but how this virus is able to evade the human immune system remains unclear. In this proposal, we will examine the role of two novel modulators of immune responses, Programmed Death-1 (PD-1) and Suppressor of Cytokine Singaling-1 (SOCS-1), in regulating T cell responses that are impaired in chronic HCV infection. This study may reveal essential mechanisms by which viruses escape human immune surveillance to establish persistent infection.