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

NK 细胞在 GBV-B 感染中的作用：HCV 清除和控制建模

• 批准号: 8509165
• 负责人: Roger Keith Reeves
• 金额: $ 26.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509165
• 关键词: Ablation; Acute; Acute Hepatitis C; Address; Africa; Alleles; Animals; Antiviral Agents; Asia; Attenuated; Autologous; Biology; Blood; Callithrix; Callithrix jacchus jacchus; Caring; Cell physiology; Cells; Chronic; Chronic Disease; Chronic Hepatitis C; Cytolysis; Data; Development; Disease; Economic Burden; Epidemiology; Exhibits; FCGR3B gene; Flavivirus; Frequencies; GB virus B; HLA-C Antigens; Hepatic; Hepatitis C; Hepatitis C virus; Hepatitis C-Like Viruses; Hepatocyte; Homeostasis; Human; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Infection; Interferons; Lead; Ligands; Liver; Liver Cirrhosis; Lymphoid; Metastatic Neoplasm to the Liver; Methods; Modality; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Organ; Pan Genus; Patients; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Play; Population; Primary carcinoma of the liver cells; Primates; Property; Regimen; Resolution; Role; Sampling; Site; Source; System; Techniques; Testing; Therapeutic; Time; Tissue Sample; Tissues; Vaccines; Viral; Viral hepatitis; Viremia; Virus; Virus Diseases; Virus Replication; cost; cytokine; cytotoxic; disease phenotype; effective therapy; helicase; in vivo; innovation; killings; mortality; nonhuman primate; novel; public health relevance; receptor; research study; response

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.

描述（由适用提供）：乙肝病毒（HCV）估计会感染全球超过1.5亿人，是全球发病率和死亡率的主要来源。在HCV感染的自然疾病病程中，许多人在急性病毒血症后清除了该病毒，而其他人则发展慢性疾病，导致肝病或肝细胞癌癌，但决定这两种疾病表型的因素却很差。由于流产感染和/或急性感染的清除发生在病毒暴露后的头几周内，因此先天免疫（例如天然杀手（NK）细胞反应）可能在决定病毒性肝炎病程中起重要作用。 Specific evidence 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 update cytotoxic functions in NK cells, and (3) patients with more细胞毒性NK细胞功能暴露了对HCV复制的更大控制。不幸的是，在进入肝组织和识别急性感染的个体方面，HCV对人类的实验研究极大地阻碍了人类。此外，黑猩猩的使用是HCV复制的唯一其他物种，通常是成本良好的，并且疾病病程显着减弱。在这项研究中，我们建议研究NK细胞在使用具有系统发育相关的病毒GBV-B的感染中感染的NK细胞在清除肝病病毒中的作用，GBV-B诱导了类似的致病性病程，许多动物赞助许多动物清除了病毒，而其他动物则持久病毒感染。这种相对便宜的小型私有模型可显着进入急性肝组织样品，并可以在体内实验中的细胞毒性NK细胞耗尽。借助控制感染时间和对急性样品和肝组织的卓越接触的能力，我们将检验以下中心假设：针对肝炎病毒的NK细胞反应的质量和数量在急性病毒清除率与慢性病中起主要作用。具体而言，我们将调查：（1） 在急性和慢性GBV-B感染期间，特定的功能和表型NK细胞库是否与病毒清除或发展为疾病有关？ （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？对这些先天因素的更清晰的了解，导致GBV-B和HCV感染的清除最终可能导致新的免疫治疗药物，药物方案和疫苗方式的发展。