Mechanisms of effective innate immunity in HCV treatment

据估计，全世界有1.7亿人感染丙型肝炎病毒。在急性丙型肝炎病毒感染后，只有15%-45%的人自发地解决了病毒。清除丙型肝炎病毒感染需要产生有效的抗病毒T细胞效应器。已知的病毒编码蛋白可诱导 外周血单核细胞的异常激活状态以及异常激活的单核细胞产生的细胞因子会对树突状细胞启动T细胞产生不利影响。在初步研究中，我们已经发现NK细胞受体的KIR家族的基因多态性及其与KIR的关系。 人类白细胞抗原(人类白细胞抗原)I类配体是自发清除丙型肝炎病毒的主要宿主决定因素；急性丙型肝炎病毒感染触发自然细胞毒性受体NKG2D的NK细胞激活途径；应激诱导的NKG2D细胞表面配体在激活的HCV上表达 外周血单核细胞。我们推测，NK细胞可能通过清除异常激活的单核细胞和病毒感染细胞，或通过促进有效的抗病毒细胞因子的形成，来促进有效的T细胞启动。此外，我们认为NK细胞的效应和细胞因子反应可能部分地由NKG2D触发，并通过抑制和激活KIR来调节，并且具有 “记忆”表型可能直接参与适应性抗病毒反应。 在这个项目中，我们将在治疗诱导的丙型肝炎根除的背景下，对NK细胞受体图谱、NK细胞效应器和记忆反应、单核细胞激活状态和细胞因子网络进行多变量分析。这些研究将使用患者的外周血液和肝脏活检标本进行，这是一项回顾性病例对照研究和前瞻性研究，目的是评估对丙型肝炎病毒感染的标准护理治疗的反应。我们希望确定：(1)控制NK细胞激活的多态受体是否预测慢性丙型肝炎患者不同的抗病毒治疗反应，以及记忆性NK细胞的获得是否与病毒根除有关；以及(2)特定的NK细胞和 单核/巨噬细胞激活和细胞因子谱有助于成功清除治疗诱导的丙型肝炎病毒感染。这些结果将与项目2中关于适应性免疫的结果相一致地进行分析。

The hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide. Following acute HCV infectton, only 15-45% of individuals resolve the virus spontaneously. Clearance of HCV infecfion requires the generation of potent antiviral T cell effectors. Virally encoded proteins are known to induce a dysregulated activation state In peripheral blood monocytes, and cytokines from aberrantly activated monocytes can adversely affect T cell priming by dendritic cells. In preliminary studies, we have shown that polymorphisms of the Killer Immunoglobulin Receptor (KIR) family of NK cell receptors and their human leukocyte antigen (HLA) class I ligands are major host determinants of spontaneous HCV clearance; that acute HCV infection triggers NK cell activation pathways involving the natural cytotoxicity receptor NKG2D; and that stress-inducible cell-surface ligands for NKG2D are expressed on HCVactivated peripheral blood monocytes. We hypothesize that NK cells may promote effective T cell priming by clearing aberrantly-activated monocytes and virally infected cells, or by contribufing to the elaboration of potent antiviral cytokines. Moreover, we propose that effector and cytokine responses of NK cells may be triggered, in part, by NKG2D and modulated by inhibitory and activating KIR, and that NK cells with a "memory" phenotype may contribute direcfiy to adaptive anfiviral responses. In this Project, we will perform mulfivariate analysis of NK cell receptor profiles, NK cell effector and memory responses, monocyte activation states, and cytokine networks in the context of treatment-induced HCV eradication. These studies will be performed using specimens of peripheral blood and liver biopsies from patients in a retrospective case-control study and a prospective study of response to standard-of care treatment of HCV infection. We wish to determine: (1) whether polymorphic receptors controlling NK cell activatton predict divergent anfiviral treatment responses in chronic HCV and whether the acquisition of memory NK cells correlates with viral eradication; and (2) whether specific NK cell and monocyte/macrophage activation and cytokine profiles contribute to successful treatment-induced clearance of HCV infectton. These results will be analyzed in concert with those obtained on adaptive immunity in Project 2.