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.

项目概要自然杀伤 (NK) 细胞凭借其以下能力提供针对病毒病原体的关键早期防御：无需事先抗原刺激即可识别并杀死病毒感染的细胞。这部分是通过两个高度多态分子之间的相互作用；杀伤细胞免疫球蛋白样受体 (KIR) 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远的影响对 HIV-1 感染过程的影响以及基于 NK 细胞的疗法根除病毒感染的功效细胞；然而，解决潜在免疫机制的动物研究受到我们的限制。了解非人类灵长类动物模型中 KIR-MHC I 类相互作用。在上一个资助期内，我们鉴定了五种恒河猴 KIR 的 MHC I 类配体，并揭示了病毒肽在抑制 NK 细胞活化作为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 类定义的猕猴 SIV 感染的反应发生变化，包括淋巴组织中受 Bw4 配体调节的 NK 细胞富集，支持高水平的病毒复制。在这里，我们以这些研究为基础来调查有关病毒影响的具体假设肽对 NK 细胞对病毒感染细胞的反应的影响以及识别 Bw4 的 NK 细胞的贡献遏制免疫缺陷病毒感染的配体。在目标 1 中，我们将定义 MHC I 类配体并分离最常见恒河猴的抗体 KIR。这一目标以最近的研究为基础，为研究 NK 提供更广泛的知识基础和关键试剂恒河猴的细胞反应。在目标 2 中，我们将研究 MHC 结合的病毒肽的影响 NK 细胞识别病毒感染细胞的 I 类配体。我们将确定在多大程度上通过稳定 MHC I 类与抑制性 KIR 结合的病毒肽来抑制 NK 细胞反应是一种某些 KIR-MHC I 类对的常见现象或独特性质，以及肽是否衍生内源表达的病毒抗原也可以影响 NK 细胞针对病毒感染细胞的活性。瞄准 3，我们将评估表达 Bw4 配体特异性 KIR 的 NK 细胞群对在 SIV 之前使用 KIR 特异性抗体消除这些细胞，从而遏制动物体内的病毒复制感染。这些史无前例的研究将有助于更好地了解 KIR- 的功能效应 MHC I 类相互作用对 NK 细胞对免疫缺陷病毒感染反应的相互作用，包括病毒的作用 NK 细胞识别病毒感染细胞中的肽以及 NK 细胞优势群体的影响 Bw4 配体对 SIV 发病机制的调节。