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: 8236131
• 负责人: Jason David Barbour
• 金额: $ 48.04万
• 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/8236131
• 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(申请人提供)：自然杀伤(NK)细胞是先天免疫反应的快速效应器。NK细胞在T细胞反应前活跃，对HIV起关键作用，并受一系列表面调节分子的调节，其中关键的是多态的KIR(杀手Ig样受体)。我们建议在一组新近感染HIV的成年人中，将KIR基因的遗传变异与疾病标记物和NK细胞功能相关联。KIR基因是由人类白细胞抗原I类等位基因连接的NK细胞的一种有效和多态的调节因子。我们的研究可能会确定NK反应是否可以被调节来提供一种新的预防艾滋病毒的模式。由于其复杂性，只有一小部分KIR基因座在HIV-1感染者中进行了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基因座及其可能的配体--HLABw4Ile80(I类等位基因的一个子集)，并产生了相反的结果。一些研究发现了相互作用提供临床保护的证据，而另一些研究则没有观察到相互作用的证据。在HIV疾病中，其他KIR基因在很大程度上还没有被发现。因此，关于KIR和NK功能在HIV中的作用，我们有有趣但不完整的信息。为了绘制这个复杂的系统图，我们将使用一种新的基于质谱学的DNA测序方法来绘制整个KIR基因簇和人类白细胞抗原I类A、B和C基因座到NK细胞的功能图谱(721.221个靶细胞系统中的NK干扰素-g、CD107a)和早期疾病标志物，在一项来自北美和巴西早期艾滋病毒感染队列的大型纵向研究中进行。我们的目标是(1)描述1300名新近感染的成人的KIR基因簇和HLAA、B、C基因座；(2)绘制这1300名成人的KIR和HLA遗传学与NK效应功能的图表；(3)对200名暴露于HIV-1的未感染成人进行KIR/HLA遗传学和NK功能检测。暴露于艾滋病毒的未感染组将能够评估KIR/人类白细胞抗原在防止感染艾滋病毒-1方面的作用以及艾滋病毒-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和人类白细胞抗原对未经治疗的B亚型感染的影响，因为治疗直到CD4+计数达到300个/uL时才开始。与公共卫生相关：先天免疫系统在控制HIV-1方面发挥着重要但尚未完全了解的作用，其中自然杀伤细胞是核心角色。通过将KIR基因定位于NK功能，我们希望找到控制HIV-1的新方法。