The role of NK cells during acute HCV infection and antiviral therapy

越来越多的证据支持先天性免疫系统在宿主对病毒性免疫应答中的核心作用。 感染.特别地，自然杀伤（NK）细胞代表关键的早期溶细胞效应细胞亚群，其是细胞毒性的主要来源。 能够自发地裂解病毒感染的细胞，而不需要预先进行Anfigen致敏。背景下 在HCV感染的过程中，少数研究集中在这一细胞亚群上，因为这些细胞已经被 这些细胞与许多病毒感染的早期控制有关，在肝脏内丰富， 除了干扰素（IFN）-α（用于治疗感染）的直接抗病毒作用外，IFN-α直接 增强NK细胞的抗病毒能力。此外，令人信服的流行病学证据已经确定， NK杀伤细胞免疫球蛋白样受体基因（KIR 2DL 3）纯合性与其 配体HLA-C等位基因的Cl家族，这表明NK细胞可能真正发挥核心作用，这种抗病毒 保护然而，NK细胞在HCV清除中的直接作用仍有待确定。 越来越多的证据表明，慢性HCV感染与一种 表型和潜在功能改变的NK细胞。然而，HCV的消退发生在第一个 在15-30%的感染者中，HCV感染持续数周至数月。这种早期的控制发生在一个时间， 适应性免疫反应才刚刚开始因此，有几个团体推测，先天的， 包括NK细胞，而不是适应性免疫应答可能在早期遏制中起主要作用。因此 本研究旨在明确NK细胞在急性HCV感染中的作用， 与清除HCV感染的能力相关的免疫学特征。因此，我们建议首先仔细 急性HCV感染中NK细胞的表型、转录和功能特征 与慢性感染者相比，解决问题的个体;然后剖析 保护KIR 2DL 3/HLA-C1组合基因型对NK细胞克隆扩增和抗病毒功能的影响; 最后，研究IFN-α和其他IFN可能如何有助于特异性扩增和功能化。 具有独特抗病毒特性的保护性NK细胞群的活化。阐明NK细胞在肿瘤治疗中的作用 丙型肝炎病毒感染的解决可能提供潜在的新机会，以提高活性， 特别是NK细胞群体，以获得对病毒的更大控制并提高HCV清除率。

Increasing evidence supports a central role for the innate immune system in the host's response against viral infections. In particular, natural killer (NK) cells represent a critical eariy cytolytic effector cell subset that are able to spontaneously lyse virally infected cells without the need for prior anfigen sensitizafion. In the context of HCV infecfion, a small number of studies have focused on this cell subset as these cells have been implicated in the eariy control of a number of viral infecfions, these cells are abundant within the liver, and that in addition to the direct antiviral effects of interferon(IFN)-a (used to treat the infection), IFN-a directly acfivates the antiviral capacity of NK cells. Furthermore, compelling epidemiologic evidence has identified a strong association between homozygosity of NK killer immunoglobulin-like receptor gene {KIR2DL3) and its ligand HLA-C alleles in the Cl family, suggesting that NK cells may truly play a central role in this antiviral protection. However the direct role of NK cells in HCV clearance still remains to be determined. Accumulating evidence suggests that chronic HCV infection is associated with the accumulafion of a phenotyplcally and potentially functionally altered NK cells. However, HCV resolution occurs within the first weeks to months of HCV infection in 15-30% of infected individuals. This eariy control occurs at a fime when the adaptive immune response is just being induced. Thus several groups have speculated that innate, including NK cells, rather than adaptive immune responses may play a major role in eariy containment. Thus in this proposal we aim to define the role of NK cells in acute HCV infecfion and to determine the NK cell immunolpgical signatures associated with the ability to clear HCV infecfion. Thus we propose to first carefully phenotyplcally, transcriptionally, and functionally characterize NK cells in acute HCV infection among individuals that resolve compared to those that become chronically infected; to then dissect the role of the protecfive KIR2DL3/HLA-C1 combined genotype on NK cell clonal expansions and antiviral funcfion; and finally to investigate how IFN-a and other IFNs may contribute to the specific expansion and funcfional activafion of protective NK cell populations with unique antiviral properties. Elucidafing the role of NK cells in the resolution of HCV infection may provide potentially novel opportunifies to enhance the activity of particular NK cell populafions to gain greater control over the virus and enhance HCV clearance rates.