Correlates of protective immunity to HCV and rational vaccine design: Project 2

项目 2. B 细胞介导的 HCV 再感染保护 尽管最近采取了高度预防措施，但预防 HCV 感染仍然是一个重要的公共卫生目标。 有效的抗病毒疗法。需要一种预防 HCV 持续存在的疫苗来阻止新出现的流行病 易感人群。回想一下，对继发性病毒感染的反应自然会模仿保护性免疫 与针对病毒抗原的疫苗接种相关的机制。我们的研究结果表明自发解决者 可能拥有抗原特异性 B 细胞，很容易被滤泡辅助 T (Tfh) 细胞激活并扩增 HCV 抗原暴露后迅速发生。然而，个体继发性 HCV 感染的治愈率较低 尽管在治疗开始时出现了 HCV 特异性 CD4 T 细胞的初始爆发，但 DAA 治愈了持续性 HCV 感染 DAA治疗。这两种情况之间的这种截然不同的回忆反应暗示了深刻的表型 DAA 处理组与 DAA 处理组之间抗原特异性记忆 T 细胞和 B 细胞反应的功能差异 未经治疗、正在解决的个人。 我们建议阐明自发抗体回忆反应的个体之间的差异 解决原发感染并随后清除其继发性 HCV 再感染 (SR/SR) 或发展 持续感染（SR/CI）。我们还将这些反应与接受 DAA 治疗的个体的反应进行比较。 治愈了持续性 HCV 感染。我们将分析两个不同 HCV 队列的纵向样本 受感染的个体进行这些研究。其中一组由注射吸毒者（PWID）组成，这些人是从 加拿大蒙特利尔，原发性 HCV 感染自行痊愈，但出现不同程度的继发性再感染 结果。另一组由来自埃及的个人组成，他们在以下情况下清除了持续性丙型肝炎病毒感染： DAA 治疗（HCV 治愈）。我们假设 SR/SR PWID 会加速和持续 记忆 B 细胞反应可产生早期广泛中和抗体 (bNAb)，有助于更快地 清除，而来自 SR/CI PWID 或 HCV 治愈个体的延迟抗体反应无法抑制病毒血症 早期，促进病毒逃脱中和作用。我们提出以下目标： 目标 1. 确定来自 B 细胞的大量和抗原特异性记忆 B 细胞的表型和转录谱 再次感染但经历不同感染后遗症的主要解决者。 目标 2. 通过对比 HCV 评估来自解析器的 HCV 特异性抗体的中和功效和广度 再感染结果。 目标 3. 确定 DAA 治疗个体感染病毒前后 B 细胞的表型和功能变化 清关。

Project 2. B Cell-Mediated Protection Against HCV Reinfection Prevention of HCV infection remains an important public health objective even with the recent adoption of highly effective antiviral therapies. A vaccine to prevent HCV persistence is needed to stem an emerging epidemic in susceptible populations. Recall responses to secondary viral infections naturally emulate the protective immune mechanisms associated with vaccination against viral antigens. Our findings suggest that spontaneous resolvers may possess antigen-specific B cells that become readily activated by T follicular helper (Tfh) cells and expand rapidly following HCV antigenic exposure. However, resolution of secondary HCV infection is low in individuals cured of persistent HCV infection by DAAs, despite an initial burst of HCV-specific CD4+ T cells at the start of DAA treatment. Such contrasting recall responses between these two scenarios implicate profound phenotypic and functional differences in antigen-specific memory T and B cell responses between DAA-treated versus untreated, resolving individuals. We propose to elucidate the differences in antibody recall responses between individuals who spontaneously resolve primary infection and subsequently either clear their secondary HCV reinfection (SR/SR) or develop persistent infection (SR/CI). We will also compare these responses to those of DAA-treated individuals who are cured of persistent HCV infection. We will analyze longitudinal samples from two separate cohorts of HCV infected individuals for these studies. One cohort consists of people who inject drugs (PWIDs) recruited from Montreal, Canada, who spontaneously resolve primary HCV infection but have different secondary reinfection outcomes. The other cohort consists of individuals from Egypt who cleared persistent HCV infection following DAA treatment (HCV-cured). We hypothesize that SR/SR PWID mount a more accelerated and sustained memory B cell response that produces early, broadly neutralizing antibodies (bNAbs) that contribute to faster clearance, while delayed antibody responses from SR/CI PWID or HCV-cured individuals fail to suppress viremia early, facilitating viral escape from neutralization. We propose the following aims: Aim 1. Determine the phenotypic and transcriptional profiles of bulk and antigen-specific memory B cells from primary resolvers who were reinfected but experienced divergent infection sequelae. Aim 2. Evaluate neutralizing efficacy and breadth of HCV-specific antibodies from resolvers with contrasting HCV reinfection outcomes. Aim 3. Determine phenotypic and functional changes in B cells of DAA-treated individuals before and after viral clearance.