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: 8293421
• 负责人: JAMES C RYAN
• 金额: $ 40.29万
• 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/8293421
• 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; receptor function; 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）：在患有丙型肝炎病毒（HCV）的急性感染中，15-30％清除了该病毒，超过70％的慢性感染进展。 HCV的分辨率受杀手型免疫球蛋白样受体（KIR）及其人类白细胞抗原（HLA）I类配体的宿主多态性的影响。已发表的基因组分析表明，KIR和HLA（因此更强的免疫力）的抑制性弱抑制性组合与HCV分辨率的增加有关，而强抑制性KIR/配体基因型与HCV慢性相关。然而，仅基因组打字就无法检查KIR生物学的至关重要的特征。首先，不同个体之间KIR定义的NK细胞子集的大小明显变化。其次，单个KIR基因中的等位基因多态性可以显着影响受体的密度和功能。第三，多个KIR的抑制作用以及激活KIR的混杂作用可以稀释离散抑制性KIR/配体对的影响。 在当前的建议中，我们采用流式细胞仪与基因组分析相结合，以检查NK细胞KIR表达和复合KIR/HLA类型对HCV分辨率的影响。我们初步研究的数据表明，自发性HCV分辨率与弱抑制受体（例如Kir2DL3）在其同源HLA-C配体的背景下的稳健NK细胞表达有关。此外，我们证明了抑制性KIR3DL受体及其HLA -A和-b配体与HCV慢性性密切相关。最高分辨率的速率是在没有混杂性抑制性KIR3DL1/HLA-A或-b对的情况下，具有弱抑制性KIR2DL/HLA-C对的复合表型。这些弱抑制性KIR/HLA类型的患者以超过50-70％的速率解决HCV，而我们的研究人群的总清除率为16％。此外，我们发现激活KIR与选定的HLA类型中的病毒清除相关，HCV分辨率的率几乎是整个队列的两倍。最后，我们的初步数据表明，与自发性HCV分辨率相关的KIR/HLA类型可能会倾向于无法清除病毒的患者中肝硬化。 基于这些引人注目的初步数据，我们提出了一项更广泛的研究，以检验基本假设，即差异NK细胞激活是HCV感染的各种结果。我们将（i）定义大量HCV患者中HCV分辨率的KIR/HLA基因型和表型相关性； （ii）定义KIR/HLA类型与慢性感染患者的治疗引起的HCV消除相关； （iii）定义了慢性感染患者中HCV肝硬化的KIR/HLA相关性； （iv）定义所选KIR/HLA相互作用对响应体外刺激的NK细胞激活和NK细胞存储器的功能效应，以及对体内急性和慢性HCV感染的响应。该提案中概述的研究检验了KIR/HLA相互作用对HCV免疫具有深远的影响，而KIR和HLA的多态性是宿主对选定感染剂的反应。这些研究还将有助于将KIR确定为药物抗病毒药疗法的有吸引力的药物靶标。 公共卫生相关性：先前的报道表明，称为KIR的不同基因会影响丙型肝炎的清除，这种病毒通常会导致慢性感染，可能导致肝硬化，肝癌和肝移植的需求。这项研究将定义KIR基因对丙型肝炎感染结果的影响，这可以帮助鉴定患者最有可能从治疗中受益，并可能导致开发新的，更有效的药物来治疗这种严重的传染病。