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

基本信息

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
项目类别：
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

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

展开

项目摘要

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）：天然杀手（NK）细胞是先天免疫反应的快速效应臂。在T细胞反应之前活跃，NK细胞对HIV起着至关重要的作用，并受到表面调节分子网络的调节，其中关键是多态KIR（杀手Ig类型受体）。我们建议将KIR的遗传变异映射为HLA I类等位基因连接的NK细胞的有效和多态性调节剂 - 在最近感染了HIV感染的成年人的队列中疾病标志物和NK细胞功能。我们的研究可能会确定是否可以调节NK响应以赋予针对HIV的新型保护方式。由于其复杂性，仅检查了HIV-1感染者的疾病或功能关联的KIR基因座的一部分。 KIR和HLA在HIV-1疾病中的作用的研究集中在Kir3ds1/Kir3dl1基因座及其假定的配体HLA BW4ILE80（I类等位基因的子集）上，并产生了对比结果。一些研究发现了提供临床保护的相互作用的证据，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。为了绘制这一复杂的系统，我们将采用一种新型的基于质谱的DNA测序方法来绘制整个KIR Gene群集和HLA I级IA，B和C基因座至NK细胞功能谱（NK IFN-G，CD107A，在721.221目标细胞系统中）和早期的CORITICTAIR中的早期CORITICTIral of North Semant of North north Seromity braz Infraz and braz and braz braz braz and braz and braz and braz and braz。我们的目标是（1）描述KIR基因簇，以及最近感染的成年人的HLA A，B和C基因座；（2）在这1300名成年人中将KIR和HLA遗传学描绘为NK效应子功能，以及（3）在200 HIV-1暴露于未感染的成年人中进行KIR/HLA遗传学和NK功能测定。受HIV暴露的未感染组将允许评估KIR/HLA在防止HIV-1采集中的作用以及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对未经治疗的亚型B感染的影响，因为直到CD4+计数为300个细胞/UL，才能开始治疗。公共卫生相关性：天然杀手细胞是中央演员的先天免疫系统，在HIV-1的控制中扮演着重要但不完全了解的角色。通过将KIR遗传学映射到NK功能，我们希望确定用于控制HIV-1的新方法。