Profiling the protective B cell response to HCV

分析保护性 B 细胞对 HCV 的反应

• 批准号: 9251760
• 负责人: Steven Foung
• 金额: $ 75.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251760
• 关键词: Acute; Animal Model; Antibodies; Antibody Response; Antibody Specificity; Antiviral Agents; B-Lymphocytes; Biochemical; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Chronic; Chronic Hepatitis C; Clone Cells; Dependency; Disease; Event; Evolution; Exhibits; Exposure to; Fc Receptor; Glycoproteins; Hepatitis C; Human; Immune; Immune response; Immunity; Immunization; Individual; Infection; Lipoproteins; Liver; Mediating; Molecular; Monoclonal Antibodies; Patients; Phase; Research; Risk; Role; Sampling; Specificity; Specimen; Time; Vaccine Design; Vaccines; Viral; Virus; Virus Receptors; Yeasts; design; high risk; human monoclonal antibodies; immunogenic; in vivo; insight; mouse model; neutralizing antibody; prevent; programs; prospective; public health relevance; receptor; response; transmission process

DESCRIPTION (provided by applicant): The Stanford Hepatitis C Cooperative Research Center will support an integrated research program focused on defining the immune correlates of protection against HCV in at-risk subjects that spontaneously clear their repeated infections. Cumulative evidence suggests that protective immunity against HCV includes both virus neutralizing (Vn) antibodies and cellular immunity. The availability of a specimen set of longitudinally collected samples from high-risk individuals followed from pre-infection to exposure followed by natural clearance or progression to chronic infection provides an unprecedented opportunity to characterize naturally-occurring immune protection. This Center will focus on the B cell response. Project 1 will analyze the specificity of the B cell responses employing high throughput isolation of Vn human monoclonal antibodies (HMAbs) by single cell cloning and by yeast display, with an emphasis on analyzing the response to the E1 glycoprotein. Functional and biochemical characterization of individual monoclonal antibodies will provide insights into the breadth of specificities of the Vn and non-Vn antibody responses, whether non-Vn antibodies interfere with Vn antibodies, and whether Vn antibodies elicited in subjects with chronic infections are more restrictive in their breadth of reactivity. Project 2 wil first explore the roles of virus-associated lipoproteins, HCV-receptor interactions, cell- to-cell transmission and non-Vn antiviral activity in modulating antibody-mediated functions; and will assess whether specific Vn or non-Vn HMAbs exhibit an antiviral effect through their Fc part by studying their ability to contribute to an antiviral effect through their interaction with Fc recepors and/or intracellular viral neutralization. Second, the project will determine the in vivo function f Vn and non-Vn HCV HMAbs in a human liver chimeric mouse model for acute HCV infection. The potency and breadth of protection of selected Vn HMAbs, single and in combination, and the ability of non-Vn HMAbs to interfere with this protection will be assessed in this small animal model of acute HCV infection. Collectively, the information gained from these studies will provide the basis for rational vaccine design, and provide much needed insights into the molecular specificities of antibodies that should be elicited by immunization.

描述（由申请人提供）：斯坦福丙型肝炎合作研究中心将支持一个综合研究项目，重点是确定高危受试者自发清除反复感染的丙型肝炎保护的免疫相关因素。累积证据表明，针对HCV的保护性免疫包括病毒中和（Vn）抗体和细胞免疫。从感染前到暴露，再到自然清除或进展到慢性感染，从高风险个体纵向收集的一组样本的可用性为描述自然发生的免疫保护提供了前所未有的机会。该中心将专注于B细胞反应。项目1将通过单细胞克隆和酵母展示技术高通量分离Vn人单克隆抗体（hmab），分析B细胞应答的特异性，重点分析对E1糖蛋白的应答。单个单克隆抗体的功能和生化特性将提供对Vn和非Vn抗体反应的特异性广度的见解，非Vn抗体是否干扰Vn抗体，以及在慢性感染受试者中引发的Vn抗体是否在其反应性广度上更具限制性。项目2将首先探索病毒相关脂蛋白、hcv受体相互作用、细胞间传递和非vn抗病毒活性在调节抗体介导功能中的作用；并将通过研究特异性Vn或非Vn hmab通过与Fc受体的相互作用和/或细胞内病毒中和来促进抗病毒作用的能力，来评估特异性Vn或非Vn hmab是否通过其Fc部分表现出抗病毒作用。其次，该项目将确定Vn和非Vn HCV hmab在人肝嵌合小鼠急性HCV感染模型中的体内功能。在这个急性HCV感染的小动物模型中，将评估选定的Vn单克隆抗体和联合克隆抗体的保护效力和广度，以及非Vn单克隆抗体干扰这种保护的能力。总的来说，从这些研究中获得的信息将为合理的疫苗设计提供基础，并为免疫应引起的抗体的分子特异性提供急需的见解。