KIR and MHC Class I Immunogenetics in SIV Infection

SIV 感染中的 KIR 和 MHC I 类免疫遗传学

• 批准号: 8760297
• 负责人: David T Evans
• 金额: $ 69.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-11-14 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760297
• 关键词: Address; Affect; Alleles; Animal Experiments; Animals; Antibodies; Avidity; Binding; Biological Assay; Biology; CD8B1 gene; Cell Count; Cells; Drug or chemical Tissue Distribution; Epitopes; Foundations; Frequencies; Genes; Genetic Polymorphism; Genome; Gut associated lymphoid tissue; HIV; HIV-1; Histocompatibility Antigens Class I; Immune; Immunogenetics; Immunologic Deficiency Syndromes; Individual; Infection; Jurkat Cells; Ligands; MHC Class I Genes; Macaca; Macaca mulatta; Mamu-A 02 antigen; Memory; Modeling; Monitor; Mutation; NK Cell Activation; Natural Killer Cells; Outcome; Pathogenesis; Peptides; Phenotype; Play; Population; Property; Reagent; Regulation; Role; SIV; Staining method; Stains; T cell response; T-Lymphocyte; Testing; Tissues; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; Work; design; killer immunoglobulin-like receptor; lymph nodes; mutant; nonhuman primate; prevent; receptor; vaccine trial

DESCRIPTION (provided by applicant): The highly polymorphic killer immunoglobulin-like receptors (KIRs) and their HLA class I ligands play a central role in the regulation of natural killer (NK) cells, and in the ability of HIV-1 infected individuals to control virus replication. However, functional studies to address the significance of KIR-MHC class I interactions in immunodeficiency virus infection have been limited by the lack of defined MHC class I ligands for KIRs in non-human primate models. We recently identified Mamu-A*02, an MHC class I molecule present in approximately 20% of Indian origin rhesus macaques, as a ligand for Mamu-KIR3DL05 (3DL05). This interaction was peptide-dependent, since Mamu-A*02 tetramers folded with certain simian immunodeficiency virus (SIV) peptides, but not others, stained primary NK cells and transfected cells expressing multiple 3DL05 alleles. Consistent with the function of an inhibitory KIR, target cells expressing Mamu-A*02 (A*02) suppressed the degranulation of tetramer-positive NK cells from 3DL05+ macaques. These observations suggest that SIV, and potentially also HIV-1, may acquire changes in epitopes that increase the avidity of MHC class I ligands for inhibitory KIRs as a mechanism of immune evasion to prevent the activation of specific NK cell subsets. Using KIR- and MHC class I-defined rhesus macaques, we will specifically address this hypothesis, as well as other questions fundamental to the biology of NK cells in immunodeficiency virus infection. The first objective of this proposal (Aim 1) is to identify additional MHC class I ligands for Mamu KIR3DL01 and -KIR3DL05; two KIRs that are commonly expressed in the rhesus macaque and for which we have identified reagents for staining these receptors on primary NK cells. This aim will build on recent work by our group to provide a broader foundation for investigating the role of KIR-MHC class I interactions in SIV infection. Our second objective (Aim 2) is to address the functional implications of viral peptides that modulate NK cell activation. We will determine the repertoire of SIV peptides that enhance or antagonize interactions with 3DL05, and will test the hypothesis that viral epitopes, which stabilize interactions with inhibitory KIRs, facilitate virus replication in the presence of NK cells bearing these receptors. Our third objective (Aim 3) is to compare longitudinal changes in 3DL05+ NK cells following SIV infection of 3DL05+/A*02+ versus 3DL05+/A*02- animals. The following questions will be addressed; Does the recognition of A*02-bound peptides stimulate or suppress the expansion of 3DL05+ NK cells? Are there phenotypic/functional differences in 3DL05+ NK cells in A*02+ versus A*02- animals? Is there a difference in the recruitment of 3DL05+ NK cells to tissues? These unprecedented studies will provide a better understanding of the importance of KIR-MHC class I interactions in immunodeficiency virus infection, and specifically the role of viral peptides in modulating NK cell activation as a mechanism of immune evasion.

描述（由申请人提供）：高度多态性的杀伤免疫球蛋白样受体（KIR）及其 HLA I 类配体在自然杀伤（NK）细胞的调节以及 HIV-1 感染者的能力中发挥着核心作用。控制病毒复制。然而，由于在非人类灵长类动物模型中缺乏明确的 KIR 的 MHC I 类配体，因此解决 KIR-MHC I 类相互作用在免疫缺陷病毒感染中的重要性的功能研究受到了限制。我们最近鉴定出 Mamu-A*02，一种 MHC I 类分子，存在于大约 20% 的印度恒河猴中，作为 Mamu-KIR3DL05 (3DL05) 的配体。这种相互作用是肽依赖性的，因为 Mamu-A*02 四聚体与某些猿猴免疫缺陷病毒 (SIV) 肽折叠，但不与其他肽折叠，对表达多个 3DL05 等位基因的原代 NK 细胞和转染细胞进行染色。与抑制性 KIR 的功能一致，表达 Mamu-A*02 (A*02) 的靶细胞抑制了 3DL05+ 猕猴四聚体阳性 NK 细胞的脱颗粒。这些观察结果表明，SIV 以及可能还有 HIV-1 可能会发生表位变化，从而增加 MHC I 类配体对抑制性 KIR 的亲和力，作为防止特定 NK 细胞亚群激活的免疫逃避机制。使用 KIR 和 MHC I 类定义的恒河猴，我们将专门解决这一假设，以及免疫缺陷病毒感染中 NK 细胞生物学的其他基本问题。 该提案的第一个目标（目标 1）是确定 Mamu 的其他 MHC I 类配体 KIR3DL01 和 -KIR3DL05；两种 KIR 通常在恒河猴中表达，我们已经鉴定出用于对原代 NK 细胞上的这些受体进行染色的试剂。这一目标将建立在我们小组最近的工作基础上，为研究 KIR-MHC I 类相互作用在 SIV 感染中的作用提供更广泛的基础。我们的第二个目标（目标 2）是解决调节 NK 细胞激活的病毒肽的功能影响。我们将确定增强或拮抗与 3DL05 相互作用的 SIV 肽库，并将测试病毒表位（稳定与抑制性 KIR 的相互作用）促进病毒的假设 在携带这些受体的 NK 细胞存在的情况下进行复制。我们的第三个目标（目标 3）是比较 3DL05+/A*02+ 与 3DL05+/A*02- 动物 SIV 感染后 3DL05+ NK 细胞的纵向变化。将解决以下问题； A*02 结合肽的识别会刺激还是抑制 3DL05+ NK 细胞的扩增？ A*02+ 与 A*02- 动物的 3DL05+ NK 细胞是否存在表型/功能差异？ 3DL05+ NK 细胞向组织的募集是否存在差异？这些前所未有的研究将有助于更好地了解 KIR-MHC I 类相互作用在免疫缺陷病毒感染中的重要性，特别是病毒肽在调节 NK 细胞中的作用 激活作为免疫逃避的机制。