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）细胞是先天免疫应答的快速效应臂。NK细胞在T细胞应答之前活跃，在对抗HIV方面发挥关键作用，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Ig样受体）。我们建议映射KIR的遗传变异-一个强大的和多态性的调节NK细胞连接的HLA I类等位基因-疾病标志物和NK细胞功能在最近感染HIV的成年人队列。我们的研究可能会确定NK反应是否可以被调节，以提供一种新的保护模式来对抗HIV。由于其复杂性，只有一小部分KIR基因座已被检查的疾病或功能协会在HIV-1感染者。关于KIR和HLA在HIV-1疾病中的作用的研究主要集中在KIR 3DS 1/KIR 3DL 1基因座及其推定配体HLA Bw 4 Ile 80（I类等位基因的子集）上，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。其他KIR基因在HIV疾病中很大程度上未被探索。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。为了绘制这个复杂的系统，我们将采用一种新的基于质谱的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，721.221靶细胞系统中的CD 107 a）和早期疾病标志物的关系，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。我们的目的是：（1）描述1300例近期感染成人的KIR基因簇，以及HLA A、B和C位点;（2）绘制这1300例成人的KIR和HLA遗传学与NK效应子功能的关系图;（3）对200例暴露于HIV-1的未感染成人进行KIR/HLA遗传学和NK功能测定。暴露于HIV的未感染组将允许评估KIR/HLA在防止HIV-1获得中的作用以及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对未治疗的B亚型感染的影响，因为治疗直到CD 4+计数达到300个细胞/μ l才开始。公共卫生相关性：先天免疫系统，其中自然杀伤细胞是一个中心演员，发挥了重要的，但不完全理解的作用，在控制艾滋病毒-1。通过将KIR遗传学映射到NK功能，我们希望确定控制HIV-1的新方法。