Mechanisms of effective innate immunity in HCV treatment

丙型肝炎病毒（HCV）慢性感染估计全世界有1.7亿人。在急性HCV感染后，只有15-45%的个体自发地消除病毒。清除HCV感染需要产生有效的抗病毒T细胞效应物。已知病毒编码的蛋白质可诱导 在外周血单核细胞中，来自异常活化的单核细胞的细胞因子可不利地影响树突细胞的T细胞引发。在初步研究中，我们已经表明NK细胞受体的杀伤免疫球蛋白受体（KIR）家族及其基因的多态性， 人类白细胞抗原（HLA）I类配体是HCV自发清除主要宿主决定因素;急性HCV感染触发涉及天然细胞毒性受体NKG 2D的NK细胞活化途径;且NKG 2D的应激诱导细胞表面配体在HCV活化的NK细胞上表达 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的细胞，或通过促进有效的抗病毒细胞因子的产生来促进有效的T细胞引发。此外，我们认为NK细胞的效应子和细胞因子应答可能部分由NKG 2D触发，并由抑制性和激活性KIR调节，并且具有NKG 2D的NK细胞可能具有抑制性和激活性KIR。 “记忆”表型可能直接有助于适应性抗病毒反应。 在本项目中，我们将在治疗诱导的HCV根除背景下对NK细胞受体谱、NK细胞效应和记忆应答、单核细胞活化状态和细胞因子网络进行多变量分析。这些研究将使用来自患者的外周血和肝活检标本进行，这些标本来自一项回顾性病例对照研究和一项对HCV感染标准治疗反应的前瞻性研究。我们希望确定：（1）控制NK细胞活化的多态性受体是否预测慢性HCV中不同的抗病毒治疗应答，以及记忆NK细胞的获得是否与病毒根除相关;以及（2）特异性NK细胞和NK细胞受体是否与HCV感染相关。 单核细胞/巨噬细胞活化和细胞因子谱有助于成功治疗诱导的HCV感染清除。这些结果将与项目2中获得的适应性免疫结果一起进行分析。

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.