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项综合研究计划，旨在定义对高风险受试者的HCV保护的免疫相关性，这些受试者自发地清除其反复感染。累积证据表明，针对HCV的保护性免疫包括中和（VN）抗体和细胞免疫。从感染前到暴露，随后自然清除或向慢性感染进展，可以提供一组纵向收集的样本的标本，从而提供了前所未有的机会，可以表征自然疾病的免疫保护。该中心将重点放在B细胞响应上。项目1将通过单细胞克隆和通过酵母显示，分析使用VN人类单克隆抗体（HMAB）的高吞吐量分离的B细胞反应的特异性，并强调分析对E1糖蛋白的反应。单个单克隆抗体的功能和生化表征将提供有关VN和非VN抗体反应的特异性广度的见解，无论非VN抗体是否干扰VN抗体，以及VN抗体是否在受试者中引起的VN抗体是否对年要感染产生了更具限制性的抗体性。项目2 WIL首先探讨了与病毒相关的脂蛋白，HCV受体相互作用，细胞到细胞传递和非VN抗病毒活性在调节抗体介导的功能中的作用；并将通过研究其与FC接收器和/或细胞内病毒中和化的相互作用来研究其FC部分通过其FC部分通过其FC部分表现出抗病毒作用的特定VN或非VN HMAB。其次，该项目将在人肝脏嵌合小鼠模型中确定体内功能F VN和非VN HCV HMAB，以用于急性HCV感染。在这种急性HCV感染的小动物模型中，评估了所选VN HMAB，单个和组合的保护效果和宽度，以及非VN HMAB干扰该保护的能力。总的来说，从这些研究中获得的信息将为理性疫苗设计提供基础，并为应通过免疫引起的抗体的分子特异性提供了急需的见解。