Dynamics of antigen specific B and Tfh responses during acute and chronic HCV

急性和慢性 HCV 期间抗原特异性 B 和 Tfh 反应的动态

• 批准号: 10063938
• 负责人: Arash Grakoui
• 金额: $ 74.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-13 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063938
• 关键词: Acute; Acute Hepatitis; Acute Hepatitis C; Adolescent and Young Adult; Antibodies; Antibody Formation; Antibody Response; Antigens; Antiviral Agents; Antiviral Therapy; Appearance; B cell differentiation; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Biological Assay; Cell Communication; Cell Count; Cell physiology; Cells; Chronic Hepatitis C; Clonal Evolution; Clonal Expansion; Clone Cells; Coculture Techniques; Collaborations; Coupled; Detection; Development; Differentiated Gene; Disease Outcome; Epidemic; Epitopes; Exhibits; Exposure to; Financial cost; Future; Gene Expression; Generations; Glycoproteins; Grant; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C Antiviral; Hepatitis C Transmission; Hepatitis C Vaccination; Hepatitis C virus; In Vitro; Incidence; Individual; Infection; Kinetics; Liver diseases; Memory B-Lymphocyte; Modeling; Molecular; Outcome; Patients; Phase; Phenotype; Plasma Cells; Process; Resolution; Role; Sampling; Structure of germinal center of lymph node; Symptoms; System; Techniques; Testing; Ursidae Family; Vaccines; Viral; Virus; Visualization; acute infection; base; chronic infection; cohort; cytokine; deep sequencing; design; effective therapy; experimental study; expression cloning; hepatitis C virus envelope 2 protein; improved; infection rate; injection drug use; intravenous drug use; longitudinal analysis; neutralizing antibody; novel; prevent; receptor; response; stem; tool; transcriptome; transmission process; trend; vaccination strategy; vaccine trial; young adult

PROJECT SUMMARY/ABSTRACT: Treatment for chronic HCV infection is now highly effective. Direct Acting Antivirals (DAA) are generally safe and most persistent infections are cured with 2-3 months of therapy. However, a strategy to control chronic hepatitis C by antiviral therapy alone is complicated by two factors. First, although antiviral therapies have improved steadily over the past 25 years, the percentage of individuals cured of chronic hepatitis C is still remarkably low in the US and globally. Almost all untreated individuals (3 million in the US, 180 million globally) are unaware of their persistent infection; there are often no symptoms of HCV infection until progressive liver disease becomes apparent many years after exposure to the virus. Second, HCV transmission has accelerated in most regions of the world. In the US, infection rates increased over the past decade because of ongoing epidemic injection drug use amongst adolescents and young adults. New undiagnosed HCV infections will almost certainly develop at a rate that outpaces detection and antiviral cure. A vaccine could help stem HCV transmission, however a complete understanding of correlates of protection is lacking. While an early appearance of broadly neutralizing antibodies (bNAbs) generally correlates with a more favorable infection outcome, the inability to isolate HCV- specific B cells to dissect their phenotype, function, receptor repertoire, gene expression and neutralization breadth has hindered the understanding of the molecular mechanisms that determine infection outcome. We have developed a novel tetramer that detects HCV E2 glycoprotein-specific memory B cells in patients infected with HCV. The objective of this grant is to define the longitudinal changes in HCV-specific B cell clonal selection and the breadth of bNAbs resulting from the interplay between HCV-specific CD4+ T follicular helper cells (Tfh) and HCV-specific B cells. Our central hypothesis is that a rapid induction of the HCV-specific Tfh cell response accelerates the selection and expansion of HCV-specific B cell clones producing bNAbs that contribute to resolution of infection. Our specific aims will test whether: HCV-specific B cells isolated longitudinally at single cell level from spontaneous resolvers are more activated, clonally focused and produce antibodies with greater neutralization breadth than HCV-specific B cells from persistently-infected patients (Aim 1); an early increase in Tfh cell activity during acute infection in spontaneous resolvers directly influences the rapid, clonal expansion of HCV-specific B cells and subsequent bNAb production (Aim 2). This study makes a significant contribution towards a vaccine-based approach designed to prevent primary HCV infection and/or reinfection.

项目概要/摘要： 目前慢性丙型肝炎病毒感染的治疗非常有效。直接作用抗病毒药物 (DAA) 通常是安全的 大多数持续性感染经过 2-3 个月的治疗即可治愈。然而，控制慢性肝炎的策略 单独使用抗病毒治疗的 C 因两个因素而变得复杂。首先，尽管抗病毒治疗有所改善 过去 25 年来，慢性丙型肝炎的治愈率仍然很低 在美国和全球。几乎所有未接受治疗的人（美国有 300 万，全球有 1.8 亿）都不知道 他们的持续感染； HCV 感染通常没有任何症状，直到出现进行性肝病为止 接触病毒多年后才明显。二是HCV传播在大部分地区加速 世界。在美国，由于持续流行的注射毒品，过去十年感染率有所上升 在青少年和年轻人中使用。几乎肯定会出现新的未确诊 HCV 感染 其速度超过了检测和抗病毒治疗的速度。疫苗可以帮助阻止丙肝病毒传播，但是 缺乏对保护相关因素的完整理解。虽然广泛中和的早期出现 抗体（bNAb）通常与更有利的感染结果相关，即无法分离 HCV- 特定 B 细胞来剖析其表型、功能、受体库、基因表达和中和作用 广度阻碍了对决定感染结果的分子机制的理解。我们 开发了一种新型四聚体，可检测感染患者体内 HCV E2 糖蛋白特异性记忆 B 细胞 与丙肝病毒。该资助的目的是定义 HCV 特异性 B 细胞克隆选择的纵向变化 以及 HCV 特异性 CD4+ T 滤泡辅助细胞 (Tfh) 之间相互作用产生的 bNAb 的广度 和HCV特异性B细胞。我们的中心假设是 HCV 特异性 Tfh 细胞反应的快速诱导 加速 HCV 特异性 B 细胞克隆的选择和扩增，产生 bNAb，从而有助于 感染的解决。我们的具体目标将测试是否： HCV 特异性 B 细胞在单次纵向分离 来自自发解析器的细胞水平更加活跃，克隆集中并产生具有更大活性的抗体 中和广度高于持续感染患者的 HCV 特异性 B 细胞（目标 1）；早期增加 自发解析器急性感染期间 Tfh 细胞的活性直接影响 Tfh 细胞的快速克隆扩增 HCV 特异性 B 细胞和随后的 bNAb 生产（目标 2）。这项研究做出了重大贡献 旨在预防原发性 HCV 感染和/或再感染的基于疫苗的方法。