KIR and MHC Class I Immunogenetics in SIV Infection

SIV 感染中的 KIR 和 MHC I 类免疫遗传学

基本信息

批准号：
10054150
负责人：
David T Evans
金额：
$ 70.42万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-11-14 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054150
关键词：
Acquired Immunodeficiency Syndrome Address Affect Allogenic Amino Acid Substitution Animal Model Animals Antibodies B-Lymphocytes Binding CD28 gene CD4 Positive T Lymphocytes Cell Therapy Cells Communicable Diseases Containment Cytoplasmic Tail Epitopes Extracellular Domain Foundations Funding Genes Genetic Polymorphism Genome HIV HIV-1 HLA-Bw4 Histocompatibility Antigens Class I Human Immune Evasion Immunize Immunogenetics Immunoglobulins Immunologic Deficiency Syndromes Immunologics Infection Killer Cells Knowledge Ligands Ligation Light Lymphoid Tissue MHC Class I Genes Macaca Macaca mulatta Modeling Mutation NK Cell Activation NK cell receptor NKB1 Natural Killer Cells Peptides Plasma Cells Plasmablast Population Predisposition Primates Property Reagent Reporter Role SIV Shapes Site Stains T-Cell Receptor Transmembrane Domain Viral Viral Antigens Viral Load result Viral Pathogenesis Virus Virus Diseases Virus Replication adeno-associated viral vector base in vivo knowledge base nonhuman primate novel pathogenic virus receptor response

项目摘要

PROJECT SUMMARY Natural killer (NK) cells provide a critical early defense against viral pathogens by virtue of their ability to recognize and kill virus-infected cells without prior antigenic stimulation. This is accomplished in part through interactions between two highly polymorphic molecules; the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their MHC class I ligands on target cells. KIR and HLA class I polymorphisms can have profound effect on the course of HIV-1 infection and the efficacy of NK cell-based therapies for eradicating virus-infected cells; however, animal studies to address underlying immunological mechanisms have been limited by our understanding of KIR-MHC class I interactions in nonhuman primate models. Over the previous funding period, we identified MHC class I ligands for five rhesus macaque KIRs and revealed a role for viral peptides in suppressing NK cell activation as a potential mechanism of immune evasion. We also observed highly dynamic changes in NK cell responses to SIV infection of KIR- and MHC class I-defined macaques, including an enrichment of NK cells regulated by Bw4 ligands in lymphoid tissues that support high levels of virus replication. Here we build on these studies to investigate specific hypotheses concerning the influence of viral peptides on NK cell responses to virus-infected cells and the contribution of NK cells that recognize Bw4 ligands to the containment of immunodeficiency virus infection. In Aim 1, we will define MHC class I ligands and isolate antibodies for the most common rhesus macaque KIRs. This aim builds on recent studies to provide a broader knowledge base and key reagents for studying NK cell responses in the rhesus macaque. In Aim 2, we will investigate the effects of viral peptides bound by MHC class I ligands on NK cell recognition of virus-infected cells. We will determine the extent to which the suppression of NK cell responses by viral peptides that stabilize MHC class I binding to inhibitory KIRs is a common phenomenon or a unique property of certain KIR-MHC class I pairs, and whether peptides derived from endogenously expressed viral antigens can also affect NK cell activity against virus-infected cells. In Aim 3, we will assess the contribution of a population of NK cells expressing a KIR specific for Bw4 ligands to the containment of virus replication in animals by depleting these cells with a KIR-specific antibody prior to SIV infection. These unprecedented studies will provide a better understanding of the functional effects of KIR- MHC class I interactions on NK cell responses to immunodeficiency virus infection, including the role of viral peptides in NK cell recognition of virus-infected cells and the impact of a dominant population of NK cells regulated by Bw4 ligands on SIV pathogenesis.

项目摘要自然杀手（NK）细胞为病毒病原体提供了关键的早期防御能力识别并杀死没有事先抗原刺激的病毒感染细胞。这部分是通过两个高度多态分子之间的相互作用；杀手细胞免疫球蛋白样受体（KIRS） NK细胞及其在靶细胞上的MHC I类配体。 KIR和HLA I类多态性可能具有深刻的对HIV-1感染过程的影响以及基于NK细胞的疗法消除病毒感染的疗效细胞；但是，我们的动物研究以解决潜在的免疫机制受到我们的限制了解非人类灵长类动物模型中KIR-MHC I类相互作用。在以前的资金期间，我们确定了五个恒河猕猴的MHC I类配体，并揭示了病毒肽在抑制NK细胞活化是免疫逃避的潜在机制。我们还观察到高度动态 NK细胞对KIR-和MHC I类定义猕猴SIV感染的反应的变化，包括由BW4配体在淋巴组织中调节的NK细胞的富集，该组织支持高水平的病毒复制。在这里，我们以这些研究为基础，以研究有关病毒影响的特定假设 NK细胞对病毒感染细胞的反应以及识别BW4的NK细胞的贡献的肽配体可控制免疫缺陷病毒感染。在AIM 1中，我们将定义MHC I类配体和最常见恒河猕猴的分离抗体 Kirs。该目标以最近的研究为基础，为研究NK提供了更广泛的知识库和关键试剂恒河猴中的细胞反应。在AIM 2中，我们将研究由MHC结合的病毒肽的作用关于病毒感染细胞的NK细胞识别的I类配体。我们将确定通过病毒肽抑制NK细胞反应，使MHC I类结合与抑制性KIRS是一个常见现象或某些KIR-MHC I类的独特特性，以及肽是否得出从内源表达的病毒抗原也可能影响NK细胞活性针对感染病毒的细胞。目标 3，我们将评估表达针对BW4配体特异性的NK细胞群的贡献通过在SIV之前用KIR特异性抗体耗尽这些细胞，可以在动物中复制病毒复制感染。这些前所未有的研究将更好地理解Kir-的功能效应 MHC I类相互作用在NK细胞对免疫缺陷病毒感染的反应上，包括病毒的作用 NK细胞识别病毒感染细胞的肽和NK细胞主要群体的影响由BW4配体在SIV发病机理上调节。