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

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)估计感染全球超过1.5亿人，是全球发病率和死亡率的主要来源。在丙型肝炎病毒感染的自然病程中，许多人在急性病毒血症后清除病毒，而另一些人则发展为慢性疾病，导致肝硬变或肝细胞癌，但决定这两种疾病表型的因素尚不清楚。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，天然免疫，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KIR2DL3及其配体HLA-C等位基因的个体对丙型肝炎病毒有更好的清除和控制；(2)治疗慢性丙型肝炎最有效的治疗方法是治疗性应用干扰素，这是一种已知激活和上调NK细胞细胞毒功能的细胞因子；(3)具有更多细胞毒性NK细胞功能的患者表现出对丙型肝炎病毒复制的更好控制。不幸的是，由于获取肝组织和识别急性感染者的困难，人类对丙型肝炎病毒的实验研究受到了显著阻碍。此外，使用黑猩猩，这是唯一可以复制丙型肝炎病毒的其他物种，通常是成本高昂的，而且病程显著减弱。在这项研究中，我们建议用一种与系统发育相关的病毒GBV-B感染普通绒猴来研究NK细胞在清除肝炎病毒中的作用，这种病毒会导致类似的致病过程，许多动物自发清除病毒，而其他动物则持续感染病毒。这种相对便宜的小型灵长类动物模型允许大量获取急性肝组织样本，并可以在体内实验中耗尽细胞毒性NK细胞。凭借控制感染时间的能力以及对急性样本和肝组织的卓越访问，我们将检验这一核心假设，即NK细胞对肝炎病毒的反应在急性病毒清除与慢性疾病的清除中发挥着主要作用。具体来说，我们将调查：(1) 急、慢性GBV-B感染过程中的特定功能和表型NK细胞是否与病毒清除或进展有关？以及(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和丙型肝炎病毒感染清除的先天因素，最终可能会导致新的免疫疗法、药物方案和疫苗模式的发展。

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.