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。以下急性 HCV感染后，只有15-45%的人自发地解决了病毒。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 外周血单核细胞和异常激活的细胞因子中的激活状态失调 单核细胞可不利地影响树突细胞对T细胞的引发。初步研究表明， NK细胞受体的杀伤免疫球蛋白受体（KIR）家族的多态性及其 人类白细胞抗原（HLA）I类配体是自发性HCV的主要宿主决定因子 急性HCV感染触发NK细胞活化途径，涉及天然细胞毒性 NKG 2D的应激诱导细胞表面配体表达于HCV激活的 外周血单核细胞我们假设NK细胞可能促进有效的T细胞启动 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。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 “记忆”表型可能直接有助于适应性抗病毒反应。 在本项目中，我们将对NK细胞受体谱、NK细胞效应子和 记忆反应，单核细胞活化状态，和细胞因子网络的背景下，治疗诱导的 HCV根除。这些研究将使用外周血和肝活检标本进行 来自一项回顾性病例对照研究和一项标准治疗反应的前瞻性研究中的患者 治疗HCV感染。我们希望确定：（1）多态性受体是否控制NK细胞 细胞活化可预测慢性HCV的不同抗病毒治疗反应， 记忆性NK细胞与病毒根除相关;（2）特异性NK细胞和 单核细胞/巨噬细胞活化和细胞因子谱有助于成功的治疗诱导 清除HCV感染。这些结果将与自适应算法得到的结果一起进行分析。 项目2的豁免权

The hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide. Following acute HCV infection, only 15-45% of individuals resolve the virus spontaneously. Clearance of HCV infection 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 HCV-activated 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 contributing 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 directly to adaptive antiviral responses. In this Project, we will perform multivariate 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 activation predict divergent antiviral 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 infection. These results will be analyzed in concert with those obtained on adaptive immunity in Project 2.