Identifying the ligand for the activating NK cell receptor KIR3DS1 and its protective role in HIV-1 disease progression

鉴定激活 NK 细胞受体 KIR3DS1 的配体及其在 HIV-1 疾病进展中的保护作用

• 批准号: 8846812
• 负责人: Wilfredo F Garcia-Beltran
• 金额: $ 3.54万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2018-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846812
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Activated Natural Killer Cell; Alleles; Area; Autoimmunity; Binding; Biochemical; Biological; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; Cell Line; Cell Surface Receptors; Cell physiology; Cells; Coculture Techniques; Collaborations; Confounding Factors (Epidemiology); Data; Disease; Disease Progression; Epidemiologic Studies; Epidemiology; Evolution; Family; Genes; Genetic; Goals; HIV; HIV-1; Immune; Immunity; Immunoglobulins; Immunoprecipitation; Immunotherapeutic agent; In Vitro; Infection; Inflammatory; Influentials; KIR3DS1; Killer Cells; Laboratories; Ligands; Literature; Lymphocyte; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Membrane Proteins; Methods; Molecular; Molecular Conformation; NK cell receptor NKB1; Natural Killer Cells; Nature; Pathogenesis; Patients; Peptides; Population; Production; Protein Binding; Proteins; Proteomics; Reporter; Research; Role; Specialist; Stimulus; Stress; Surface Plasmon Resonance; Surveys; System; Testing; Transplantation; Ursidae Family; Validation; Viral; Virus; Virus Diseases; Work; base; cell type; combat; cytokine; cytotoxicity; human disease; innovation; insight; killings; member; novel; novel therapeutic intervention; pathogen; public health relevance; receptor; receptor binding; screening

 DESCRIPTION (provided by applicant): Natural killer (NK) cells and their receptors have been gaining prominence in the HIV field as more connections to HIV acquisition, progression, and viral evolution are being uncovered. One early finding in the field was that HIV-1-infected patients possessing the activating NK cell receptor KIR3DS1 and certain HLA class I alleles have a significantly slower progression to AIDS. Subsequent research has shown that KIR3DS1 triggers NK cell-mediated killing and cytokine production, and work from our group has demonstrated that KIR3DS1- expressing NK cells in co-culture with HIV-1-infected CD4+ T cells have a superior ability to suppress viral replication when certain HLA class I alleles are present. However, no one has been able to show an isolated interaction between KIR3DS1 and HLA class I. This has hampered our mechanistic understanding of how KIR3DS1 confers protection in HIV-1 pathogenesis and leaves open many possibilities as to what is triggering and interacting with KIR3DS1. Thus, the present goal of this study is to discover the KIR3DS1 ligand. To this end, we will implement a battery of unbiased, innovative, and complementary molecular biological and cellular immunological approaches - including use of soluble fusion constructs, reporter cells, and immunoprecipitation and mass spectrometry - to robustly identify the KIR3DS1 ligand. In addition, we aim to determine the cellular conditions that induce the expression of KIR3DS1 ligands in HIV-1 and other disease settings in which KIR3DS1 has been shown to be involved (e.g. other viral infections, cancer, autoimmunity, transplantation). This wil provide mechanistic insights as to how NK cell function is regulated through KIR3DS1:ligand interactions and, ultimately, elucidate how KIR3DS1 is able to slow HIV-1 disease progression, providing a new basis for NK cell-centered immunotherapeutic strategies that can help treat or control HIV/AIDS.

 描述（由申请人提供）：随着越来越多的与 HIV 获得、进展和病毒进化的联系被发现，自然杀伤 (NK) 细胞及其受体在 HIV 领域越来越受到重视。该领域的一项早期发现是 HIV-拥有激活 NK 细胞受体 KIR3DS1 和某些 HLA I 类等位基因的 1 感染患者，其进展为 AIDS 的速度明显减慢。后续研究表明，KIR3DS1 会触发 NK 细胞介导的杀伤和杀伤作用。细胞因子的产生以及我们小组的工作表明，当某些 HLA I 类等位基因存在时，表达 KIR3DS1 的 NK 细胞与 HIV-1 感染的 CD4+ T 细胞共培养时具有抑制病毒复制的优异能力。 然而，没有人能够证明 KIR3DS1 和 HLA I 类之间存在孤立的相互作用。这阻碍了我们对 KIR3DS1 如何在 HIV-1 发病机制中提供保护的机制理解，并为什么触发 KIR3DS1 并与 KIR3DS1 相互作用留下了许多可能性。因此，本研究目前的目标是发现 KIR3DS1 配体 为此，我们将实施一系列公正、创新和互补的分子生物学和细胞免疫学方法 - 包括使用。可溶性融合构建体、报告细胞以及免疫沉淀和质谱分析——以稳健地鉴定 KIR3DS1 配体 此外，我们的目标是确定在 HIV-1 和 KIR3DS1 存在的其他疾病环境中诱导 KIR3DS1 配体表达的细胞条件。已被证明参与其中（例如其他病毒感染、癌症、自身免疫、移植），这将为 NK 细胞功能如何通过调节提供机制见解。 KIR3DS1：配体相互作用，并最终阐明 KIR3DS1 如何能够减缓 HIV-1 疾病的进展，为以 NK 细胞为中心的免疫治疗策略提供新的基础，从而帮助治疗或控制 HIV/艾滋病。