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: 8417022
• 负责人: Jason David Barbour
• 金额: $ 67.74万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417022
• 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; 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

ABSTRACT 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.

抽象的 天然杀手（NK）细胞是先天免疫反应的快速效应臂。 T细胞之前活跃 反应，NK细胞对HIV起关键作用，并由表面调节网络调节 分子，其中包括多态KIR（杀伤Ig样受体）。我们建议映射遗传 KIR的变化 - 一种由HLA I类等位基因连接的NK细胞的有效和多态性调节剂 - 疾病 最近感染了HIV的成年人队列中的标记和NK细胞功能。我们的研究可能会确定NK是否 可以调节反应以赋予针对HIV的新型保护方式。 由于其复杂性，仅检查了KIR基因座的一部分疾病或功能关联 在HIV-1感染者中。关于KIR和HLA在HIV-1疾病中的作用的研究集中在 KIR3DS1/KIR3DL1基因座及其推定的配体HLA BW4ILE80（I类等位基因的子集），并产生 对比的结果。一些研究发现了提供临床保护的相互作用的证据，而 其他人则没有观察到相互作用的证据。其他KIR基因在HIV疾病中基本上没有探索。 因此，我们有关于KIR和NK功能在HIV中的作用的有趣但不完整的信息。 为了绘制这个复杂的系统，我们将采用一种新型的基于质谱的DNA测序方法 绘制整个KIR基因簇和HLA I类A，B和C基因座至NK细胞功能曲线（NK IFN-G， 在721.221目标细胞系统中的CD107A和早期疾病标志物中的1500名成年人的纵向研究中 来自北美和巴西早期艾滋病毒感染队列。我们的目标是描述KIR基因簇， 以及1300年最近感染的成年人的HLA A，B和C基因座； （2）将KIR和HLA遗传学绘制到NK效应器 在这1300名成年人中的功能和（3）在200组中执行KIR/HLA遗传学和NK功能测定 HIV-1暴露于未感染的成年人。艾滋病毒暴露的未感染组将允许评估 KIR/HLA可防止HIV-1获取以及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研究KIR和HLA对未治疗的亚型B感染的影响，因为治疗不是 启动直到CD4+计数为300个单元/UL。