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: 8991842
• 负责人: Wilfredo F Garcia-Beltran
• 金额: $ 3.63万
• 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/8991842
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Activated Natural Killer Cell; Alleles; Area; Autoimmunity; Binding; Binding Proteins; 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; Proteins; Proteomics; Reporter; Research; Role; Specialist; Stimulus; Stress; Surface Plasmon Resonance; Surveys; System; Testing; Transplantation; Ursidae Family; Validation; Viral; Virus; Virus Diseases; Virus Replication; 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）：随着与HIV获得、进展和病毒进化的更多联系被发现，自然杀伤（NK）细胞及其受体在HIV领域日益突出。该领域的一个早期发现是，具有活化NK细胞受体KIR 3DS 1和某些HLA I类等位基因的HIV-1感染患者向AIDS的进展明显较慢。随后的研究表明，KIR 3DS 1触发NK细胞介导的杀伤和细胞因子的产生，我们小组的工作表明，当存在某些HLA I类等位基因时，与HIV-1感染的CD 4 + T细胞共培养的表达KIR 3DS 1的NK细胞具有上级抑制病毒复制的能力。 然而，还没有人能够证明KIR 3DS 1与HLA I类之间存在孤立的相互作用。这阻碍了我们对KIR 3DS 1如何在HIV-1发病机制中提供保护的机械理解，并留下了许多关于触发KIR 3DS 1并与之相互作用的可能性。因此，本研究的目的是发现KIR 3DS 1配体。为此，我们将实施一系列无偏见，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，免疫沉淀和质谱-以稳健地识别KIR 3DS 1配体。此外，我们的目标是确定诱导KIR 3DS 1配体在HIV-1和其他疾病环境中表达的细胞条件，其中KIR 3DS 1已被证明参与（例如，其他病毒感染，癌症，自身免疫，移植）。这将提供关于NK细胞功能如何通过KIR 3DS 1：配体相互作用调节的机制见解，并最终阐明KIR 3DS 1如何能够减缓HIV-1疾病进展，为可以帮助治疗或控制HIV/AIDS的以NK细胞为中心的免疫策略提供新的基础。