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: 8466277
• 负责人: JAMES C RYAN
• 金额: $ 38.42万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466277
• 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 Targeting; 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; Inflammatory; Killer Cells; Lead; Ligands; Link; 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 inflammation; 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.

描述（由申请人提供）：在丙型肝炎病毒（HCV）急性感染中，15-30%的病毒被清除，70%以上进展为慢性感染。 HCV 分辨率受杀伤性免疫球蛋白样受体 (KIR) 及其人类白细胞抗原 (HLA) I 类配体的宿主多态性影响。已发表的基因组分析表明，KIR 和 HLA 的弱抑制组合（因此更强的免疫力）与 HCV 消退率增加相关，而强抑制 KIR/配体基因型与 HCV 慢性相关。然而，仅靠基因组分型无法检验 KIR 生物学的极其重要的特征。首先，不同个体之间 KIR 定义的 NK 细胞亚群的大小存在显着差异。其次，单个 KIR 基因的等位基因多态性可以显着影响受体密度和功能。第三，多个 KIR 的组合抑制作用以及激活 KIR 的混杂作用可以削弱离散抑制性 KIR/配体对的作用。 在当前的提案中，我们采用流式细胞术结合基因组分析来检查 NK 细胞 KIR 表达和复合 KIR/HLA 类型对 HCV 分辨率的影响。我们的初步研究数据表明，HCV 自发消退与 NK 细胞中弱抑制性受体（例如 KIR2DL3）在其同源 HLA-C 配体中的强劲表达有关。此外，我们证明抑制性 KIR3DL 受体及其 HLA-A 和 -B 配体与 HCV 慢性化密切相关。在不存在混杂的抑制性 KIR3DL1/HLA-A 或 -B 对的情况下，具有弱抑制性 KIR2DL/HLA-C 对的化合物表型具有最高的分辨率。具有这些弱抑制性 KIR/HLA 类型的患者 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 类型的病毒清除率相关，HCV 清除率几乎是整个队列的两倍。最后，我们的初步数据表明，与 HCV 自发消退相关的 KIR/HLA 类型可能会导致无法清除病毒的患者发生肝硬化。 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来检验这一基本假设：NK 细胞激活差异是 HCV 感染不同结果的基础。我们将 (i) 在一大群 HCV 患者中定义 HCV 消退的 KIR/HLA 基因型和表型相关性； (ii) 定义与慢性感染患者中治疗诱导的 HCV 根除相关的 KIR/HLA 类型； (iii) 确定慢性感染患者中 HCV 肝硬化的 KIR/HLA 相关性； (iv) 定义选定的 KIR/HLA 相互作用对 NK 细胞活化和 NK 细胞记忆的功能影响，以响应体外刺激，以及响应体内急性和慢性 HCV 感染。本提案中概述的研究检验了以下假设：KIR/HLA 相互作用对 HCV 免疫具有深远而非适度的影响，并且 KIR 和 HLA 的多态性是宿主对选定传染源的反应的基础。这些研究还将有助于将 KIR 确定为药物抗病毒疗法的有吸引力的药物靶点。