Discovery and Targeting of West Nile Virus Epitopes

西尼罗河病毒表位的发现和靶向

• 批准号: 8459018
• 负责人: William Hildebrand
• 金额: $ 99.91万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-09 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459018
• 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

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）：I类人白细胞抗原（HLA）几乎存在于每个细胞的表面。它们的功能是将细胞内适应性传递给淋巴细胞，否则这些淋巴细胞无法进入细胞内空间以检测病毒。I类HLA分子通过首先对细胞内的蛋白质的肽片段取样来暴露病毒感染。然后I类分子进入细胞表面，并将这些细胞内蛋白片段展示给T淋巴细胞。连续扫描细胞表面的I类HLA的细胞毒性T淋巴细胞能够挑出携带病毒衍生肽的I类HLA，然后破坏感染的细胞。I类HLA通过在细胞表面呈递病毒肽表位来揭示细胞内病毒。我们的实验室致力于鉴定那些感染细胞特有的肽表位。我们认为，准确发现感染细胞特有的病毒表位将促进病毒治疗剂的成功下游开发。为了验证这一假设，我们在本项目的目标1中提出发现西尼罗河病毒（WNV）感染细胞特有的I类HLA呈递肽表位。我们将使用中空纤维生物反应器和质谱鉴定多个I类HLA中的WNV表位。为了启动我们发现的WNV感染细胞特有的表位的治疗开发，在目标2中，我们提出了产生区分感染细胞的WNV/HLA I类复合物的单克隆抗体。目标2中的抗WNV/HLA复合物mAb的开发将通过与Receptor Logic（一家精通HLA/肽复合物mAb生产的生物技术公司）合作进行。该项目的总体目标是用mAb治疗性靶向WNV感染的细胞，并且在目标3中，我们将测试这些mAb在体内破坏WNV感染的细胞的能力。将用WNV感染HLA转基因小鼠，将被动施用针对WNV肽/HLA复合物的mAb，并将评价抗体介导的病毒感染细胞的破坏。

项目成果

A novel T-cell receptor mimic defines dendritic cells that present an immunodominant West Nile virus epitope in mice.

一种新型 T 细胞受体模拟物定义了在小鼠体内呈现免疫显性西尼罗病毒表位的树突状细胞。

• DOI: 10.1002/eji.201444450
• 发表时间: 2014
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Kim,Sojung;Pinto,AmeliaK;Myers,NancyB;Hawkins,Oriana;Doll,Krysten;Kaabinejadian,Saghar;Netland,Jason;Bevan,MichaelJ;Weidanz,JonA;Hildebrand,WilliamH;Diamond,MichaelS;Hansen,TedH
• 通讯作者: Hansen,TedH

Surface phenotype and functionality of WNV specific T cells differ with age and disease severity.

• DOI: 10.1371/journal.pone.0015343
• 发表时间: 2010-12-13
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Piazza P;McMurtrey CP;Lelic A;Cook RL;Hess R;Yablonsky E;Borowski L;Loeb MB;Bramson JL;Hildebrand WH;Rinaldo CR
• 通讯作者: Rinaldo CR

Immunodominant West Nile Virus T Cell Epitopes Are Fewer in Number and Fashionably Late.

• DOI: 10.4049/jimmunol.1501821
• 发表时间: 2016-05-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kaabinejadian S;McMurtrey CP;Kim S;Jain R;Bardet W;Schafer FB;Davenport JL;Martin AD;Diamond MS;Weidanz JA;Hansen TH;Hildebrand WH
• 通讯作者: Hildebrand WH