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Human Cytomegalovirus Entry Glycoprotein Complexes

人巨细胞病毒进入糖蛋白复合物

基本信息

批准号：
8702328
负责人：
Theodore S Jardetzky
金额：
$ 24.08万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-13 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702328
关键词：
Accounting Acquired Immunodeficiency Syndrome Affect Affinity Antibodies Antibody Formation Antigens B-Lymphocytes Binding Binding Sites Cell surface Cells Cellular Membrane Cellular Tropism Complex Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Disease Endothelial Cells Epithelial Cells Epitopes Epstein-Barr Virus Infections Family Fetus Fibroblasts Foundations Glycoproteins Herpesviridae Human Human Herpesvirus 4 Human Herpesvirus 6 Immune response Immunocompetent Individual Infection Knowledge Laboratories Lead Left Life Location Maps Membrane Molecular Molecular Chaperones Nature Pathology Patients Peptides Play Population Pregnancy Preparation Proteins Reagent Receptor Activation Research Role Route Simplexvirus Site Specificity Structure Subgroup Subunit Vaccines Therapeutic Intervention Tissues Transplant Recipients Tropism Viral Viral Fusion Proteins Viral Proteins Virus Virus Assembly Virus Diseases Woman analog cell type comparative experience gammaherpesvirus in vivo infected B cell inhibitor/antagonist insight neutralizing antibody novel novel strategies pathogen protein complex public health relevance receptor receptor binding response therapeutic development tissue tropism vaccine development virus tropism

项目摘要

DESCRIPTION (provided by applicant): This proposal represents a new research direction on HCMV entry glycoproteins for the Jardetzky Laboratory, which has previously had extensive prior effort focusing on understanding Epstein-Barr virus (EBV) entry into target cells and on developing novel approaches to therapeutic intervention. The entry of HCMV into epithelial and endothelial cells requires the formation of a pentameric viral glycoprotein complex comprised of the gH, gL, UL128, UL130, and UL131 proteins (gHgL/UL128-131). This pentameric complex is a functional analog of the EBV gHgL/gp42 complex, which targets EBV to infect B cells. HCMV gHgL also assembles into a trimeric complex with the gO protein, which has a broader functional role, affecting virus entry into fibroblasts, epithelial cells and endothelial cells. Th Jardetzky Laboratory has conducted extensive crystallographic and functional studies of the EBV gHgL and gp42 complexes and demonstrated that EBV infection can be blocked with a gp42-derived high affinity peptide inhibitor. We now propose to conduct similar studies of the HCMV gHgL, gHgL/gO and gHgL/UL128-131 complexes, as well as examine the interaction of HCMV gHgL complexes with neutralizing antibodies. These studies will further our understanding of herpesvirus entry mechanisms and may lead to new routes to developing HCMV entry inhibitors or gHgL subunit vaccines.

描述（由申请人提供）：该提案代表了Jardetzky实验室关于HCMV进入糖蛋白的新研究方向，该实验室此前已进行了广泛的前期工作，重点是了解EB病毒（EBV）进入靶细胞和开发新的治疗干预方法。HCMV进入上皮和内皮细胞需要形成由gH、gL、UL 128、UL 130和UL 131蛋白组成的五聚体病毒糖蛋白复合物（gHgL/UL 128 -131）。该五聚体复合物是EBV gHgL/gp 42复合物的功能类似物，其靶向EBV以感染B细胞。HCMV gHgL还与gO蛋白组装成三聚体复合物，其具有更广泛的功能作用，影响病毒进入成纤维细胞、上皮细胞和内皮细胞。Jardetzky实验室已经对EBV gHgL和gp 42复合物进行了广泛的晶体学和功能研究，并证明EBV感染可以用gp 42衍生的高亲和力肽抑制剂阻断。我们现在建议对HCMV gHgL、gHgL/gO和gHgL/UL 128 -131复合物进行类似的研究，以及检查HCMV gHgL复合物与中和抗体的相互作用。这些研究将进一步加深我们对疱疹病毒进入机制的理解，并可能导致开发HCMV进入抑制剂或gHgL亚单位疫苗的新途径。