Role of NK Cells in GBV-B Infection: Modeling HCV Clearance and Control

描述（由申请人提供）：据估计，丙型肝炎病毒（HCV）感染全球超过1.5亿人，是全球发病率和死亡率的主要来源。在HCV感染的自然病程中，许多人在急性病毒血症后清除病毒，而另一些人则发展成慢性疾病，导致肝硬化或肝细胞癌，但决定这两种疾病表型的因素知之甚少。由于流产感染和/或急性感染的清除发生在病毒暴露后的第一周内，先天免疫，如自然杀伤（NK）细胞反应，可能在决定病毒性肝炎的病程中发挥重要作用。NK细胞作用的具体证据包括：（1）流行病学证据表明，表达NK受体KIR 2DL 3及其配体HLA-C等位基因的个体具有更好的HCV清除和控制，（2）慢性HCV的最有效治疗是干扰素治疗性给药。已知激活和上调NK细胞中的细胞毒性功能的细胞因子，和（3）具有更多细胞毒性NK细胞功能的患者表现出对HCV复制的更大控制。不幸的是，在人类中的HCV的实验研究是显着阻碍了难以进入肝组织和在确定急性感染的个人。此外，使用黑猩猩（HCV将在其中复制的唯一其他物种）通常成本高昂，并且疾病过程显著减弱。在这项研究中，我们提出了调查的作用，NK细胞在清除肝炎病毒感染的普通绒猴与遗传相关的病毒，GBV-B，诱导一个类似的致病性疾病的过程中，许多动物自发清除病毒，而其他人有持续的病毒感染。这种相对便宜的小型灵长类动物模型允许大量获得急性肝组织样本，并且可以在实验上耗尽体内的细胞毒性NK细胞。通过控制感染时间的能力和对急性样本和肝组织的上级访问，我们将检验中心假设，即针对肝炎病毒的NK细胞应答的质量和数量在急性病毒清除与慢性疾病中起主要作用。具体来说，我们将研究：（1） 急性和慢性GBV-B感染期间特异性功能和表型NK细胞库是否与病毒清除或疾病进展相关？（2）细胞毒性NK细胞是否抑制GBV-B复制并有助于控制或解决GBV-B感染？更清楚地了解这些导致GBV-B和HCV感染清除的先天因素，最终可能导致新的免疫治疗剂，药物治疗方案和疫苗模式的开发。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is estimated to infect greater than 150 million people worldwide and is a major source of global morbidity and mortality. During the natural disease course of HCV infection, many individuals clear the virus after an acute viremia, while others develop chronic disease resulting in cirrhosis of the liver or hepatocellular carcinoma, but the factors that dictate these two disease phenotypes are poorly understood. Because abortive infections and/or clearance of acute infections occur within the first weeks after virus exposure, innate immunity, such as natural killer (NK) cell responses, are likely to play a significant role in dictating the disease course of viral hepatitis. Specific evidnce of a role for NK cells includes: (1) epidemiologic evidence demonstrating that individuals expressing alleles for the NK receptor KIR2DL3 and its ligand HLA-C have better clearance and control of HCV, (2) the most effective treatment for chronic HCV is therapeutic administration of interferon-¿, a cytokine known to activate and upregulate cytotoxic functions in NK cells, and (3) patients with more cytotoxic NK cell functions exhibit greater control of HCV replication. Unfortunately, experimental study of HCV in humans is significantly hindered by difficulty in accessing liver tissues and in identifying acutely infected individuals. Furthermore, the use of chimpanzees, the only other species in which HCV will replicate, is generally cost-prohibitive and the disease course is significantly attenuated. In this study we propose to investigate the role of NK cells in clearing Hepaciviruses using infection of common marmosets with a phylogenetically related virus, GBV-B, that induces a similar pathogenic disease course where many animals spontaneously clear the virus while others have persistent viral infection. This relatively inexpensive small primate model allows significant access to acute liver tissue samples and can be experimentally depleted of cytotoxic NK cells in vivo. With the ability to control for time of infection and superior access to acute samples and liver tissue we will test th central hypothesis that the quality and quantity of NK cell responses against Hepaciviruses play a major role in acute viral clearance versus chronic disease. Specifically we will investigate: (1) Are specific functional and phenotypic NK cell repertoires during acute and chronic GBV-B infection associated with viral clearance or progression to disease? and (2) Do cytotoxic NK cells inhibit GBV-B replication and contribute to control or resolution of GBV-B infection? A clearer understanding of these innate factors that lead to clearance of GBV-B and HCV infections could ultimately lead to development of new immunotherapeutics, drug regimens and vaccine modalities.