Neutralizing antibody responses during natural control of acute hepatitis B with and without HIV-1 coinfection

在有或没有 HIV-1 合并感染的急性乙型肝炎自然控制过程中中和抗体反应

基本信息

批准号：
10674691
负责人：
Justin Richard Bailey
金额：
$ 79.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674691
关键词：
Acute Hepatitis Adult Affect Affinity Antibodies Antibody Formation Antibody Response B cell repertoire B-Cell Antigen Receptor B-Lymphocytes Binding Biological Assay Biological Models Blood Cell Culture Techniques Cell Separation Characteristics Chronic Chronic Hepatitis B Cirrhosis Cohort Studies Data Development Epitopes Evolution Frequencies HIV HIV Antibodies HIV Infections HIV Seronegativity HIV-1 HepG2 Hepatitis B Hepatitis B Antibodies Hepatitis B Infection Hepatitis B Surface Antigens Hepatitis B Virus Human Immune response Immunocompetent Immunoglobulin Somatic Hypermutation In Vitro Infection Knowledge Length Maps Measures Molecular Monoclonal Antibodies Outcome Participant Persons Plasma Prevalence Primary carcinoma of the liver cells Recovery Research Resources Risk Role Sampling Sorting Specimen Surface Antigens System Techniques Testing Time Translating Viral Virus Diseases Visit acute infection chronic infection co-infection cohort comparison control follow-up human subject innovation men neutralizing antibody next generation sequencing novel novel strategies polyclonal antibody prospective response success

项目摘要

Summary This proposal aims to understand the effects of HIV on the humoral immune response to hepatitis B by focusing on HBV-specific neutralizing antibodies (NAb), B cell repertoire, and monoclonal antibodies that develop after an acute hepatitis B infection. This proposal will study 185 men (74 HIV+) in the MACS-WIHS Combined Cohort Study who had acute hepatitis B while in follow-up and whose outcome of either natural recovery (n=163) or viral persistence (n=22) was previously determined. The first Aim focuses on comparing the prevalence and magnitude of the anti-HBs NAb responses over 30 months after natural control of an acute HBV infection in people living with and without HIV. We hypothesize that in persons living with HIV (PLWH), the NAb responses will be weaker and less durable than in persons without HIV infection. Decreased durability of NAb responses could contribute to the increased risk of HBV reactivation with HIV infection. In the second Aim, we will tag HBV specific B cells isolated from participants’ specimens obtained during their acute infection period. We will then determine and compare the molecular features of HBV-specific B cell receptors during the acute infection period between those with natural recovery and those who develop chronic hepatitis B. We will also determine the effects of HIV on these molecular features and on frequency of B cells specific for HBV. In the third Aim, we will clone monoclonal antibodies (mAbs) from these HBV-specific B cells and determine the mAbs’ functional characteristics and binding affinities. We expect that the mAbs from persons with natural recovery will bind with higher affinity and neutralize more potently than those who develop chronic infection. We also expect that HIV will decrease the affinity and potency of the mAbs. Innovative aspects of this project include: 1) The unique cohort of a large number of incident HBV infections where both natural recovery and viral persistence occur in prospectively-followed people living with and without HIV infection, 2) The ability to detect NAb responses in plasma from human subjects using the HepG2-NTCP infection model system, and 3) The ability to isolate HBV-specific B cells for ex vivo study. To date, such studies have not been possible explaining why there is little information on NAb responses to HBV obtained directly from infected humans. The results from this proposal will contribute to our understanding of the effects of HIV on the immune response to hepatitis B and could facilitate future research to develop a functional cure for hepatitis B, which is the leading cause of cirrhosis and hepatocellular carcinoma worldwide.

概括该提案旨在通过以下方式了解艾滋病毒对乙型肝炎体液免疫反应的影响专注于 HBV 特异性中和抗体 (NAb)、B 细胞库和单克隆抗体，该提案将研究 MACS-WIHS 中的 185 名男性（74 名 HIV+）。联合队列研究在随访期间患有急性乙型肝炎，其自然结果先前确定了恢复 (n=163) 或病毒持久性 (n=22)。第一个目标侧重于比较。急性疾病自然控制后 30 个月内抗 HBs NAb 反应的流行率和程度艾滋病毒感染者和未感染者的乙肝病毒感染情况我们勇敢面对艾滋病毒感染者 (PLWH) 的情况，与未感染 HIV 的人相比，NAb 反应会更弱且更不持久。第二，NAb 反应的减少可能会增加 HIV 感染导致 HBV 再激活的风险。目标是，我们将对从参与者急性感染期间获得的标本中分离出的 HBV 特异性 B 细胞进行标记然后我们将确定并比较在此期间 HBV 特异性 B 细胞受体的分子特征。自然康复者与慢性乙型肝炎患者之间的急性感染期。我们将还确定了 HIV 对这些分子特征以及 HBV 特异性 B 细胞频率的影响。第三个目标，我们将从这些 HBV 特异性 B 细胞中克隆单克隆抗体 (mAb)，并确定单克隆抗体的功能特征和结合亲和力我们期望来自具有天然特征的单克隆抗体。与慢性感染者相比，康复者将以更高的亲和力结合并更有效地中和。我们还预计 HIV 会降低单克隆抗体的亲和力和效力。该项目的创新点包括：1）大量乙型肝炎病毒感染事件的独特队列在有或没有感染病毒的预期跟踪人群中，自然恢复和病毒持续存在的情况 HIV 感染，2) 使用 HepG2-NTCP 检测人类受试者血浆中的 NAb 反应的能力感染模型系统，以及 3) 分离 HBV 特异性 B 细胞用于离体研究的能力。研究尚无法解释为什么有关 HBV 的 NAB 反应的信息很少该提案的结果将有助于我们了解其影响。 HIV 对乙型肝炎免疫反应的影响，可能有助于未来开发功能性治愈方法的研究乙型肝炎是全世界肝硬化和肝细胞癌的主要原因。