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

项目总结/摘要： 治疗慢性HCV感染现在非常有效。直接作用抗病毒药物（DAA）通常是安全的， 大多数持续性感染通过2-3个月的治疗治愈。然而，控制慢性肝炎的策略 C单用抗病毒治疗并发症有两个因素。首先，尽管抗病毒疗法已经有所改善， 在过去的25年里，慢性丙型肝炎治愈的百分比仍然非常低 在美国和全球。几乎所有未经治疗的人（美国300万，全球1.8亿）都不知道 他们的持续感染;通常没有HCV感染的症状，直到进行性肝病成为 在接触病毒多年后才出现。其次，HCV传播在大多数地区加速， 世界在美国，由于持续的流行性注射药物， 在青少年和年轻人中使用。新的未确诊的HCV感染几乎肯定会在 其速度超过了检测和抗病毒治疗。疫苗可以帮助阻止HCV传播，但是， 对保护的相关因素缺乏全面的了解。虽然早期出现的广泛中和 抗体（bNAb）通常与更有利的感染结果相关，不能分离HCV- 特异性B细胞，以剖析其表型、功能、受体库、基因表达和中和 广泛性阻碍了对决定感染结果的分子机制的理解。我们 已经开发了一种新的四聚体，用于检测感染患者中HCV E2糖蛋白特异性记忆B细胞 HCV。这项资助的目的是确定HCV特异性B细胞克隆选择的纵向变化 以及HCV特异性CD 4+滤泡辅助性T细胞（Tfh）之间相互作用产生的bNAb的宽度 和HCV特异性B细胞。我们的中心假设是HCV特异性Tfh细胞应答的快速诱导 加速HCV特异性B细胞克隆的选择和扩增，产生有助于 感染的解决。我们的具体目标是测试是否：HCV特异性B细胞纵向分离， 来自自发消退者的细胞水平更加活化，克隆集中，并产生抗体， 持续感染患者的HCV特异性B细胞的中和宽度（目的1）; 自发消退者急性感染期间Tfh细胞活性直接影响tfh的快速克隆性扩增， HCV特异性B细胞和随后的bNA B产生（目的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。

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.