HCV resolution correlates with patterned KIR expressions on lymphocytes.

HCV 分辨率与淋巴细胞上的 KIR 模式表达相关。

• 批准号: 7889750
• 负责人: JAMES C RYAN
• 金额: $ 40.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889750
• 关键词: Accounting; Acute; Acute Hepatitis C; Affect; Affinity; Antiviral Therapy; B-Lymphocytes; Binding; Biology; CD8B1 gene; Cell surface; Cells; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Clonal Expansion; Communicable Diseases; Competence; Data; Development; Drug Delivery Systems; Family; Flow Cytometry; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; HCV Cirrhosis; HLA Antigens; Hepatitis C; Hepatitis C Antibodies; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Immunophenotyping; In Vitro; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Killer Cells; Lead; Ligands; Link; Liver; Liver Cirrhosis; Liver Failure; Lymphocyte; MHC Class I Genes; Malignant neoplasm of liver; Memory; Metabolic Clearance Rate; NK Cell Activation; NK cell receptor NKB1; Natural Killer Cells; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Population; Population Study; Proteins; Publishing; Receptor Gene; Reporting; Resistance; Resolution; Risk; Role; Stimulus; Subgroup; T-Lymphocyte; Testing; Therapeutic; Treatment outcome; Viral; Virus; Virus Diseases; base; cellular targeting; cohort; cytotoxic; defined contribution; human leukocyte antigen gene; imprint; in vivo; inhibitor/antagonist; killer immunoglobulin-like receptor; leukocyte antigen typing; liver transplantation; neoplastic; pathogen; programs; public health relevance; receptor; receptor density; receptor expression; response; success; viral RNA

DESCRIPTION (provided by applicant): In acute infection with hepatitis C virus (HCV), 15-30% clear the virus and more than 70% progress to chronic infection. HCV resolution is influenced by host polymorphisms of killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands. Published genomic analyses suggest that weak inhibitory combinations of KIR and HLA (and hence stronger immunity) are associated with increasing rates of HCV resolution, while strong inhibitory KIR/ligand genotypes are associated with HCV chronicity. Genomic typing alone fails to examine critically important features of KIR biology, however. First, there is marked variability in the size of KIR-defined NK cell subsets among different individuals. Second, allelic polymorphisms in individual KIR genes can markedly affect receptor density and function. Third, the combined inhibitory effects of multiple KIR, as well as confounding effects of activating KIR, can dilute effects of discrete inhibitory KIR/ligand pairs. In the current proposal, we employ flow cytometry combined with genomic analyses to examine the effects of NK cell KIR expression and compound KIR/HLA types on HCV resolution. Data from our preliminary studies show that spontaneous HCV resolution is associated with the robust NK cell expression of weakly inhibitory receptors such as KIR2DL3 in the context of their cognate HLA-C ligands. In addition, we demonstrate that inhibitory KIR3DL receptors and their HLA-A and -B ligands are strongly associated with HCV chronicity. The highest resolution rates are in compound phenotypes with weak inhibitory KIR2DL/HLA-C pairs in the absence of confounding inhibitory KIR3DL1/HLA-A or -B pairs. Patients with these weak inhibitory KIR/HLA types resolve HCV at rates exceeding 50- 70%, compared with an overall clearance rate of 16% in our study population. Further, we find that activating KIR correlate with viral clearance in selected HLA types, with HCV resolution rates nearly twice those of the overall cohort. Finally, our preliminary data show that KIR/HLA types associated with spontaneous HCV resolution may predispose to cirrhosis among patients who fail to clear the virus. Based upon these compelling preliminary data, we propose a broader study to test the fundamental hypothesis that differential NK cell activation underlies diverse outcomes of HCV infection. We will (i) define KIR/HLA genotypic and phenotypic correlates of HCV resolution in a large cohort of HCV patients; (ii) define KIR/HLA types correlated with treatment induced HCV eradication among chronically infected patients; (iii) define KIR/HLA correlates of HCV cirrhosis among chronically infected patients; and (iv) define the functional effects of selected KIR/HLA interactions on NK cell activation and NK cell memory in response to in vitro stimuli, and in response to acute and chronic HCV infection in vivo. The studies outlined in this proposal test the hypothesis that KIR/HLA interactions have profound, rather than modest effects on HCV immunity, and that polymorphisms of KIR and HLA underlie host responses to selected infectious agents. These studies also will help to identify KIR as attractive drug targets for pharmacologic antiviral therapies. PUBLIC HEALTH RELEVANCE: Previous reports showed that different genes known as KIR influence the clearance of hepatitis C, a virus that typically causes chronic infection that can lead to liver cirrhosis, liver cancer and the need for liver transplantation. This study will define the effects of KIR genes on the outcome of hepatitis C infection, which could help identify the patients most likely to benefit from treatment and also could lead to the development of new, more effective drugs to treat this serious infectious disease.

描述（由申请人提供）：在丙型肝炎病毒（HCV）急性感染中，15-30%的人清除病毒，70%以上进展为慢性感染。HCV的消退受宿主杀伤免疫球蛋白样受体（KIR）及其人类白细胞抗原（HLA）I类配体多态性的影响。已发表的基因组分析表明，KIR和HLA的弱抑制性组合（因此具有更强的免疫力）与HCV消退率增加相关，而强抑制性KIR/配体基因型与HCV慢性化相关。然而，单独的基因组分型不能检查KIR生物学的关键重要特征。首先，在不同的个体中，KIR定义的NK细胞亚群的大小存在显著的差异。其次，单个KIR基因的等位基因多态性可显著影响受体密度和功能。第三，多种KIR的组合抑制作用以及活化KIR的混杂作用可以稀释离散抑制性KIR/配体对的作用。 在目前的建议中，我们采用流式细胞术结合基因组分析来研究NK细胞KIR表达和复合KIR/HLA类型对HCV分辨率的影响。来自我们的初步研究的数据显示，自发的HCV消退与弱抑制性受体如KIR 2DL 3在其同源HLA-C配体的背景下的强NK细胞表达相关。此外，我们证明抑制性KIR 3DL受体及其HLA-A和-B配体与HCV慢性化密切相关。在不存在混杂抑制性KIR 3 DL 1/HLA-A或-B对的情况下，具有弱抑制性KIR 2 DL/HLA-C对的复合表型的分辨率最高。具有这些弱抑制性KIR/HLA类型的患者的HCV消退率超过50- 70%，而我们研究人群的总体清除率为16%。此外，我们发现激活KIR与选定HLA类型的病毒清除相关，HCV消退率几乎是整个队列的两倍。最后，我们的初步数据显示，与自发性HCV消退相关的KIR/HLA类型可能使未能清除病毒的患者易患肝硬化。 基于这些令人信服的初步数据，我们提出了一个更广泛的研究，以测试的基本假设，差异NK细胞激活的基础上的HCV感染的不同结果。我们将（i）在一个大的HCV患者队列中确定HCV消退的KIR/HLA基因型和表型相关性;（ii）在慢性感染患者中确定与治疗诱导的HCV根除相关的KIR/HLA类型;（iii）在慢性感染患者中确定HCV肝硬化的KIR/HLA相关性;和（iv）确定所选KIR/HLA相互作用对NK细胞活化和NK细胞记忆响应体外刺激的功能作用，以及对体内急性和慢性HCV感染的应答。本提案中概述的研究验证了KIR/HLA相互作用对HCV免疫力具有深远而非适度影响的假设，以及KIR和HLA多态性是宿主对选定感染因子反应的基础。这些研究也将有助于确定KIR作为药物抗病毒治疗的有吸引力的药物靶点。 公共卫生相关性：以前的报告表明，不同的基因被称为KIR影响丙型肝炎的清除，丙型肝炎病毒通常会导致慢性感染，导致肝硬化，肝癌和肝移植的需要。这项研究将确定KIR基因对丙型肝炎感染结果的影响，这可能有助于确定最有可能从治疗中受益的患者，也可能导致开发新的，更有效的药物来治疗这种严重的传染病。