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.

摘要 自然杀伤（NK）细胞是先天免疫反应的快速效应臂。T细胞前活化 NK细胞在对抗HIV的反应中起着关键作用，并受到表面调控网络的调控。 分子，其中关键的多态性KIR（杀手Ig样受体）。我们建议绘制基因图谱 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--与疾病的变化 标志物和NK细胞功能在最近感染HIV的成年人队列。我们的研究可能会决定朝鲜是否 可以调节免疫应答，以提供针对HIV的新的保护模式。 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 HIV-1感染者。关于KIR和HLA在HIV-1疾病中的作用的研究集中在 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），并已产生了 对比结果。一些研究发现了相互作用的证据，从而提供了临床保护， 其他人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 为了将整个KIR基因簇和HLA I类A、B和C基因座与NK细胞功能谱（NKIFN-γ， 721.221靶细胞系统中的CD 107 a）和早期疾病标志物， 来自北美和巴西的早期HIV感染队列。我们的目的是（1）描述KIR基因簇， 1300例近期感染者的HLA A、B、C位点的检测结果：（2）绘制NK细胞免疫反应（KIR）和HLA遗传学图 在这1300名成人中进行KIR/HLA遗传学和NK功能测定 未感染HIV-1的成年人。暴露于艾滋病毒的未感染组将允许评估以下因素的作用： KIR/HLA对HIV-1感染的保护作用及HIV-1感染对NK功能的影响我们的巴西 队列研究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，因为治疗不是 启动直至CD 4+计数为300个细胞/μ l。