Discovery and Targeting of West Nile Virus Epitopes

西尼罗河病毒表位的发现和靶向

基本信息

批准号：
8245072
负责人：
William Hildebrand
金额：
$ 115.97万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-09 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245072
关键词：
Academia Animal Testing Animals Antibodies Antiviral Agents B-Lymphocytes Biological Assay C57BL/6 Mouse Categories Cell Lineage Cell surface Cells Collaborations Complex Cytotoxic T-Lymphocytes Defect Development Diagnosis Diagnostic Diamond Epitopes Family Fever Fiber Flaviviridae Future Generations Goals HLA Antigens Human Human Development Hybridomas Immune response Immune system Immunotherapeutic agent In Vitro Individual Industry Infection Intracellular Space Laboratories Lead Life Cycle Stages Logic Lymphocyte Mass Spectrum Analysis Mediating Meningoencephalitis Mission Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease Neurologic Pathogenesis Peptide Fragments Peptides Physicians Population Principal Investigator Production Proteins Research Personnel Rodent Sampling Scanning Seroprevalences Specificity Surface Survivors T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Testing Texas Therapeutic Therapeutic Intervention Time Transgenic Mice Transgenic Organisms Universities Vaccines Viral Viral Proteins Virulent Virus Virus Diseases Washington West Nile virus base catalyst experience fitness in vivo microbial mouse model neutralizing antibody novel novel strategies pathogen pre-clinical programs receptor research clinical testing response therapeutic development vaccine development virus infection mechanism

项目摘要

DESCRIPTION (provided by applicant): Class I Human Leukocyte Antigens (HLA) is found on the surface of virtually every cell. Their function is to convey intracellular fitness to lymphocytes that cannot otherwise access intracellular spaces in order to detect viruses. Class I HLA molecules expose a viral infection by first sampling peptide fragments of proteins within the cell. Class I molecules then egress to the cell surface and display these intracellular protein snippets to T lymphocytes. Cytotoxic T lymphocytes which continuously scan class I HLA at the cell surface are able to single out class I HLA carrying virus-derived peptides and then destroy infected cells. Class I HLA reveals intracellular viruses by presenting viral peptide epitopes at the cell surface. Our laboratory is devoted to identifying those peptide epitopes unique to infected cells. We posit that the accurate discovery of viral epitopes unique to infected cells will facilitate the successful downstream development of viral therapeutics. To test this hypothesis, we propose to discover class I HLA presented peptide epitopes unique to West Nile Virus (WNV) infected cells in aim 1 of this project. We will identify WNV epitopes in multiple class I HLA using hollow fiber biorectors and mass spectroscopy. In order to initiate therapeutic development of the epitopes we find unique to WNV infected cells, in aim 2 we propose the generation of monoclonal antibodies to WNV/HLA class I complexes that distinguish infected cells. The development of mAb to WNV/HLA complexes in aim 2 will proceed through collaboration with Receptor Logic, a biotech firm proficient in the production of mAb to HLA/peptide complexes. The overall objective of this project is to therapeutically target WNV infected cells with mAb, and in aim 3 we will test these mAb for their ability to destroy WNV infected cells in vivo. HLA transgenic mice will be infected with WNV, mAb to WNV peptide/HLA complexes will be passively administered, and the antibody-mediated destruction of virus-infected cells will be evaluated.

描述（由申请人提供）：几乎每个细胞的表面上都发现了I类人白细胞抗原（HLA）。它们的功能是将细胞内适应性传达给无法进入细胞内空间以检测病毒的淋巴细胞。 I类HLA分子通过首先采样细胞内蛋白质的肽片段暴露了病毒感染。 I类分子然后出口到细胞表面，并将这些细胞内蛋白质片段显示在T淋巴细胞中。在细胞表面连续扫描I类HLA的细胞毒性T淋巴细胞能够将携带病毒衍生肽的I类置于I类，然后破坏受感染的细胞。 I类HLA通过在细胞表面呈现病毒肽表位来揭示细胞内病毒。我们的实验室致力于鉴定受感染细胞独有的肽表位。我们认为，被感染细胞独有的准确发现病毒表位将促进病毒疗法的成功下游发展。为了检验这一假设，我们建议在该项目的AIM 1中发现I类HLA呈现的肽表位（WNV）感染细胞。我们将使用中空纤维生物学和质谱法确定多个I级HLA中的WNV表位。为了启动表位的治疗发展，我们发现WNV感染细胞独有，在AIM 2中，我们提出了与WNV/HLA I类配合物的单克隆抗体的产生，从而区分受感染细胞。 AIM 2中MAB向WNV/HLA复合物的开发将通过与受体逻辑的合作（一家熟练生产MAB生产HLA/肽复合物生产的生物技术公司）来进行。该项目的总体目的是用MAB治疗靶向WNV感染的细胞，在AIM 3中，我们将测试这些MAB的体内破坏WNV感染细胞的能力。 HLA转基因小鼠将被WNV感染，将被动地给予WNV肽/HLA复合物，并评估抗体介导的病毒感染细胞的破坏。