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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结