Decryption of KIR genetics and function in early HIV-1 infection

解密早期 HIV-1 感染中的 KIR 遗传学和功能

• 批准号: 8011425
• 负责人: Jason David Barbour
• 金额: $ 24.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011425
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Alleles; American; Base Sequence; Biological Assay; Biology; Brazil; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Line; Cell physiology; Cells; Clinical; Complex; DNA Fingerprinting; DNA Sequence; Data; Disease; Disease Marker; Eye; Frequencies; Future; Gene Cluster; Genes; Genetic; Genetic Variation; Genotype; Goals; HIV; HIV Infections; HIV-1; Health; Human; Immune; Immune response; Immune system; Immunogenetics; Individual; Infection; Interferon Type II; Joints; KIR3DS1; Left; Ligands; Longitudinal Studies; MALDI-TOF Mass Spectrometry; Maps; Mass Spectrum Analysis; Mediating; Methods; NK cell receptor NKB1; Natural Killer Cells; North America; Pattern; Persons; Phase; Phenotype; Play; Population; Population Study; Prevention; RNA; Receptor Gene; Reporting; Research; Risk; Role; Route; San Francisco; Stratification; Surface; System; T cell response; T-Cell Activation; Time; United States National Institutes of Health; Variant; Work; adaptive immunity; arm; base; cohort; killer T cell; multidisciplinary; novel; programs; protective effect; receptor; research study; response

DESCRIPTION (provided by applicant): The Natural Killer (NK) cell is a rapid effector arm of the innate immune response. Active before T cell responses, NK cells play a critical role against HIV and are regulated by a network of surface regulatory molecules, key among them the polymorphic KIR (killer Ig-like receptor). We propose to map the genetic variation of KIR - a potent and polymorphic regulator of NK cells ligated by HLA Class I alleles - to disease markers and NK cell function in a cohort of recently HIV-infected adults. Our research may determine if the NK response can be modulated to confer a novel mode of protection against HIV. Due to its complexity, only a fraction of KIR loci have been examined for disease or functional associations in HIV-1 infected persons. Studies on the role of KIR and HLA in HIV-1 disease have focused on the KIR3DS1/KIR3DL1 loci and its putative ligand, HLA Bw4Ile80 (a subset of Class I alleles), and have yielded contrasting results. Some studies have found evidence of an interaction conferring clinical protection, while others have observed no evidence for an interaction. Other KIR genes are largely unexplored in HIV disease. Hence, we have intriguing but incomplete information about the role of KIR and NK function in HIV. To chart this complex system, we will employ a novel mass spectrometry-based DNA sequencing method to chart the entire KIR gene cluster and the HLA Class I A, B, and C loci to NK cell functional profile (NK IFN-g, CD107a in a 721.221 target cell system) and early disease markers in a large, longitudinal study of 1500 adults from a North American and Brazilian early HIV infection cohort. We aim (1) To describe the KIR gene cluster, and the HLA A, B and C loci in 1300 recently infected adults; (2) To chart KIR and HLA genetics to NK effector function in these 1300 adults and (3) To perform KIR/HLA genetics and NK functional assays in a group of 200 HIV-1 exposed uninfected adults. The HIV-exposed uninfected group will allow assessment of the role of KIR/HLA in protection against HIV-1 acquisition and effects of HIV-1 infection on NK function. Our Brazil cohort enables us to further examine KIR and HLA effects on untreated subtype B infection, as treatment is not initiated until a CD4+ count of 300 cells/ul. PUBLIC HEALTH RELEVANCE: The innate immune system, of which the Natural Killer cell is a central actor, plays an important but incompletely understood role in the control of HIV-1. By mapping KIR genetics to NK function we hope to identify novel methods for the control of HIV-1.

描述（由申请人提供）：自然杀伤（NK）细胞是先天免疫反应的快速效应臂。 NK 细胞在 T 细胞反应之前活跃，在对抗 HIV 方面发挥着关键作用，并受到表面调节分子网络的调节，其中关键是多态性 KIR（杀伤性 Ig 样受体）。我们建议将 KIR（一种由 HLA I 类等位基因连接的 NK 细胞的有效多态性调节因子）的遗传变异映射到最近感染 HIV 的成年人群体中的疾病标志物和 NK 细胞功能。我们的研究可能会确定是否可以调节 NK 反应以提供一种新的艾滋病毒保护模式。由于其复杂性，仅对一小部分 KIR 基因座进行了 HIV-1 感染者疾病或功能关联的检查。关于 KIR 和 HLA 在 HIV-1 疾病中的作用的研究主要集中在 KIR3DS1/KIR3DL1 基因座及其推定配体 HLA Bw4Ile80（I 类等位基因的子集）上，并得出了相反的结果。一些研究发现了相互作用的证据，可提供临床保护，而另一些研究则没有观察到相互作用的证据。其他 KIR 基因在 HIV 疾病中很大程度上尚未被探索。因此，我们对 KIR 和 NK 功能在 HIV 中的作用有有趣但不完整的信息。为了绘制这个复杂系统的图表，我们将采用一种新颖的基于质谱的 DNA 测序方法来绘制整个 KIR 基因簇和 HLA I 类 A、B 和 C 基因座与 NK 细胞功能谱（NK IFN-g、CD1​​07a）的图表。 721.221 靶细胞系统）和早期疾病标记物，这是一项对来自北美和巴西早期 HIV 感染队列的 1500 名成年人进行的大型纵向研究。我们的目标 (1) 描述 1300 名最近感染的成年人的 KIR 基因簇以及 HLA A、B 和 C 基因座； (2) 绘制这 1300 名成年人中 KIR 和 HLA 遗传学与 NK 效应器功能的关系图，以及 (3) 在 200 名暴露于 HIV-1 的未感染成年人中进行 KIR/HLA 遗传学和 NK 功能测定。暴露于 HIV 的未感染组将能够评估 KIR/HLA 在防止 HIV-1 感染方面的作用以及 HIV-1 感染对 NK 功能的影响。我们的巴西队列使我们能够进一步检查 KIR 和 HLA 对未经治疗的 B 亚型感染的影响，因为直到 CD4+ 计数达到 300 个细胞/ul 才开始治疗。公共卫生相关性：先天免疫系统（自然杀伤细胞是其中的核心角色）在 HIV-1 的控制中发挥着重要但尚未完全了解的作用。通过将 KIR 遗传学映射到 NK 功能，我们希望找到控制 HIV-1 的新方法。