Mechanisms of antibody-mediated control of repeated hepatitis C virus infection in humans

抗体介导控制人类丙型肝炎病毒重复感染的机制

• 批准号: 10398151
• 负责人: Justin Richard Bailey
• 金额: $ 54.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398151
• 关键词: Affinity; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Antigenic Variation; Antigens; Autologous; Automobile Driving; B cell repertoire; B-Cell Activation; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Binding Sites; Biological Assay; Blocking Antibodies; CD4 Positive T Lymphocytes; CD81 gene; Cells; Chronic; Clone Cells; Collaborations; Complex; Development; Disease Outcome; Epitopes; Evolution; Exposure to; Flow Cytometry; Functional disorder; HIV-1; Hepatitis C; Hepatitis C Antibodies; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune; Immune response; Immunoglobulin Somatic Hypermutation; In Vitro; Individual; Infection; Infusion procedures; Link; Measures; Mediating; Modeling; Monoclonal Antibodies; Participant; Phenotype; Plasma; Play; Proteins; Resistance; Role; Site; Stimulus; Study Subject; T cell response; T-Lymphocyte; Testing; Time; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; Work; adaptive immunity; base; chronic infection; env Gene Products; high dimensionality; human subject; in vivo; neutralizing antibody; novel; pressure; response; single-cell RNA sequencing; vaccine candidate; vaccine development; vaccine response

Project Summary Broadly neutralizing antibodies (bNAbs) block infection by diverse HCV strains in vitro, and infusion of bNAbs is protective against HCV infection in animal models. In contrast to some other chronic viral infections like HIV- 1 where bNAbs do not appear to influence disease outcome, early development of high plasma bNAb titers is associated with spontaneous clearance of primary HCV infection in humans. Although it is clear that bNAbs can play a critical role in clearance of primary HCV infection, detailed analysis of antibody titers, epitopes targeted, and B cell phenotypes associated with clearance of infection are still lacking. Individuals who clear multiple reinfections may be the ideal study subjects to further define protective antibody responses. Of those who clear their first infection, 80% clear subsequent reinfections with a rapid rise in neutralizing antibody (NAb) titers, shorter duration of infection, and lower peak viremia, demonstrating protective adaptive immunity that can serve as a model for a desired vaccine response. It is not known which parameters of the B cell response are most critical for repeated clearance of infection, or what antigenic stimuli are necessary for induction of these responses. In Aim 1 of this proposal, we will define plasma anti-HCV antibody binding and neutralizing activity associated with repeated clearance of reinfection. In Aim 2, we will determine the mechanistic basis for changes in neutralizing activity by characterizing the dynamic interplay between the circulating B cell repertoire and HCV sequence changes during reinfection. In Aim 3, we will define phenotypes of HCV-specific B cells associated with repeated clearance of reinfection. Because reinfections are generally cleared very efficiently, these immune responses can serve as a model for responses that should be induced by a vaccine. By characterizing plasma antibody responses, B cell repertoires, viral antigenic variation, and B cell phenotypes in human subjects with repeated spontaneous clearance of infection, we will inform HCV vaccine development.

项目概要 广泛中和抗体 (bNAb) 可在体外阻断多种 HCV 毒株的感染，并可输注 bNAb 在动物模型中具有预防 HCV 感染的作用。与艾滋病毒等其他一些慢性病毒感染相比， 1 如果 bNAb 似乎不影响疾病结果，则血浆 bNAb 滴度的早期发展是 与人类原发性 HCV 感染的自发清除有关。尽管bNAbs很明显 可在清除原发性 HCV 感染中发挥关键作用，详细分析抗体滴度、表位 仍然缺乏与感染清除相关的靶向性和 B 细胞表型。清除的个人 多次再感染可能是进一步定义保护性抗体反应的理想研究对象。其中 清除首次感染的人，80% 清除随后的再感染，中和抗体 (NAb) 迅速上升 滴度、感染持续时间较短和病毒血症峰值较低，证明了保护性适应性免疫 可以作为所需疫苗反应的模型。目前尚不清楚 B 细胞反应的哪些参数 对于重复清除感染最关键，或者什么抗原刺激对于诱导感染是必需的 这些回应。 在该提案的目标 1 中，我们将定义血浆抗 HCV 抗体结合和中和活性相关的 反复清除再感染。在目标 2 中，我们将确定变化的机制基础 通过表征循环 B 细胞库和 HCV 之间的动态相互作用来中和活性 再感染期间序列发生变化。在目标 3 中，我们将定义相关 HCV 特异性 B 细胞的表型 反复清除再感染。 由于再感染通常可以非常有效地清除，因此这些免疫反应可以作为模型 疫苗应引起的反应。通过表征血浆抗体反应，B 细胞 重复自发性人类受试者的病毒库、病毒抗原变异和 B 细胞表型 清除感染后，我们将通知丙型肝炎疫苗的开发。