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: 10205733
• 负责人: Justin Richard Bailey
• 金额: $ 51.63万
• 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/10205733
• 关键词: Affinity; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Antigenic Variation; Antigens; Antiviral Agents; 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; Structure; 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.

项目摘要 在体外不同的HCV菌株和bnabs输注的大量中和抗体（BNAB）块感染 可以保护动物模型中的HCV感染。与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，那么高血浆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。虽然很明显bnabs 可以在清除原发性HCV感染，抗体滴度，表位的详细分析中发挥关键作用 仍缺乏与感染清除相关的靶向和B细胞表型。很清楚的人 多次重新发现可能是进一步定义保护性抗体反应的理想研究对象。那些 谁清除了他们的第一次感染，有80％的人随后清除后续恢复，中和抗体（NAB）的迅速增加 滴度，较短的感染持续时间和较低的峰值病毒血症，证明了保护性适应性免疫，表明 可以用作所需疫苗反应的模型。尚不清楚B细胞响应的哪些参数 对于重复清除感染最重要，或者对于诱导哪种抗原刺激 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 重复清除重新感染。在AIM 2中，我们将确定更改的机械基础 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 恢复期间的序列变化。在AIM 3中，我们将定义与HCV特异性B细胞的表型 重复清除重新感染。 由于通常非常有效地清除恢复原状，因此这些免疫反应可以作为模型 应由疫苗诱导的反应。通过表征血浆抗体反应，B细胞 人类受试者的曲目​​，病毒抗原变异和B细胞表型反复自发 清除感染，我们将告知HCV疫苗开发。