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

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