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）：高度多态杀手型免疫球蛋白样受体（KIRS）及其HLA I类配体在调节天然杀伤（NK）细胞的调节中起着核心作用，以及HIV-1感染个体控制病毒复制的能力。但是，由于缺乏在非人类灵长类动物模型中，缺乏确定的MHC I类配体，因此无法解决免疫缺陷病毒感染中KIR-MHC I类相互作用的重要性。我们最近确定了MAMU-A*02，这是一种MHC I类分子，其中约20％的印度恒河猕猴是Mamu-Kir3DL05（3DL05）的配体。这种相互作用是肽依赖性的，因为MAMU-A*02四聚体用某些SIMIAN免疫缺陷病毒（SIV）肽折叠，而不是其他肽染色的原代NK细胞和表达多个3DL05等位基因的转染细胞。与抑制性KIR的功能一致，表达MAMU-A*02（A*02）的靶细胞抑制了从3DL05+猕猴对四聚体阳性NK细胞的脱粒。这些观察结果表明，SIV或可能也可能获得HIV-1，可能会获取表位的变化，从而增加了MHC I类配体的抑制性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类定义的恒河猕猴，我们将专门解决这一假设，以及其他问题，是免疫缺陷病毒感染中NK细胞生物学基础的其他问题。 该提案的第一个目标（AIM 1）是确定MAMU的其他MHC I类配体 KIR3DL01和-KIR3DL05;在恒河猕猴中通常表达的两个KIR，我们已经确定了在原代NK细胞上染色这些受体的试剂。这个目标将以我们小组的最新工作为基础，为研究KIR-MHC I类互动在SIV感染中的作用提供了更广泛的基础。我们的第二个目标（AIM 2）是解决调节NK细胞激活的病毒肽的功能意义。我们将确定增强或拮抗3DL05相互作用的SIV肽的曲目，并将检验以下假设，即病毒表位稳定与抑制性KIR的相互作用的假设促进了病毒 在带有这些受体的NK细胞存在下复制。我们的第三个目标（AIM 3）是比较3DL05+/A*02+与3DL05+/A*02-动物SIV感染后3DL05+ NK细胞中的纵向变化。将解决以下问题； *02结合肽的识别是否会刺激或抑制3DL05+ NK细胞的膨胀？在A*02+与A*02-动物中，3DL05+ NK细胞中是否存在表型/功能差异？ 3DL05+ NK细胞募集到组织是否有差异？这些前所未有的研究将更好地理解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 激活作为免疫逃避机制。