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: 8088134
• 负责人: JAMES C RYAN
• 金额: $ 40.53万
• 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/8088134
• 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(申请人提供)：在急性丙型肝炎病毒感染中，15%-30%的病毒清除，70%以上进展为慢性感染。丙型肝炎病毒的分解受宿主的杀伤免疫球蛋白样受体(KIR)及其人类白细胞抗原(HLAI)类配体的多态性的影响。已发表的基因组分析表明，KIR和HLA的弱抑制组合(因此具有较强的免疫力)与提高丙型肝炎病毒的分离率有关，而强抑制的KIR/配体基因型与丙型肝炎病毒的慢性化有关。然而，仅靠基因组分型并不能检验KIR生物学的关键重要特征。首先，KIR定义的NK细胞亚群的大小在不同个体之间存在显著差异。其次，个体KIR基因的等位基因多态性可以显著影响受体的密度和功能。第三，多个KIR的联合抑制效应以及激活KIR的混杂效应可以冲淡离散抑制KIR/配体对的作用。在目前的方案中，我们使用流式细胞术结合基因组分析来检测NK细胞KIR的表达和KIR/HLA复合类型对丙型肝炎病毒解析的影响。我们初步研究的数据表明，自发的丙型肝炎病毒溶解与NK细胞在其同源HLA-C配体的背景下强烈表达弱抑制受体如KIR2DL3有关。此外，我们还证明了抑制性KIR3DL受体及其HLA-A和-B配体与丙型肝炎病毒的慢性化密切相关。在没有混合抑制KIR3DL1/HLA-A或-B对的情况下，具有弱抑制KIR2DL/HLA-C对的复合表型的分辨率最高。这些弱抑制性KIR/HLA型患者的丙型肝炎病毒消退率超过50-70%，而在我们的研究人群中，总体清除率为16%。此外，我们发现在选定的人类白细胞抗原类型中，激活KIR与病毒清除相关，丙型肝炎病毒的清除率几乎是整个队列的两倍。最后，我们的初步数据显示，在未能清除病毒的患者中，与自发的丙型肝炎病毒溶解相关的KIR/HLA型可能易患上肝硬变。基于这些令人信服的初步数据，我们提出了一项更广泛的研究，以检验基本假设，即不同的NK细胞激活是导致丙型肝炎病毒感染的不同结果的基础。我们将(I)确定在大量丙型肝炎患者中KIR/HLA基因型别和表型与丙型肝炎病毒消退的相关性；(Ii)确定与慢性感染患者中治疗诱导的丙型肝炎根除相关的KIR/HLA型；(Iii)确定慢性感染患者中丙型肝炎硬化的KIR/HLA相关性；以及(Iv)确定选定的KIR/HLA相互作用在响应体外刺激和体内急、慢性丙型肝炎感染时对NK细胞激活和NK细胞记忆的功能影响。这项建议中概述的研究验证了这样的假设，即KIR/HLA相互作用对丙型肝炎病毒免疫有深远的影响，而不是轻微的影响，KIR和HLA的多态是宿主对选定的感染性病原体的反应的基础。这些研究还将有助于确定KIR是药理抗病毒治疗的有吸引力的药物靶点。 与公共卫生相关：以前的报告显示，被称为KIR的不同基因会影响丙型肝炎病毒的清除。丙型肝炎病毒通常会导致慢性感染，导致肝硬化、肝癌和需要进行肝移植。这项研究将确定KIR基因对丙型肝炎感染结局的影响，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。