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

• 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
• 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

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 该提案旨在了解HIV对乙型肝炎对乙型肝炎的影响的影响 专注于HBV特异性中和抗体（NAB），B细胞库和单克隆抗体 急性丙型肝炎感染后发展。该建议将在Macs-Wihs中研究185名男性（74 HIV+） 在随访中患有急性乙型肝炎的组合队列研究，其自然结果的结果 先前确定了恢复（n = 163）或病毒持久性（n = 22）。第一个目的是比较 自然控制急性后30个月内，抗HBS NAB反应的患病率和大小 患有和没有艾滋病毒的人的HBV感染。我们假设在患有艾滋病毒（PLWH）的人中 与没有HIV感染的人相比，NAB反应将弱且耐用。耐用性降低 NAB反应的可能导致HIV感染HBV重新激活的风险增加。在第二个 目的，我们将标记从参与者在急性感染中获得的标本中分离出的HBV特异性B细胞 时期。然后，我们将确定并比较HBV特异性B细胞受体的分子特征 自然恢复患者和患有慢性丙型肝炎的患者之间的急性感染期。我们将 还要确定HIV对这些分子特征的影响以及对HBV特异性的B细胞的频率。在 第三目的是，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 mabs的功能特征和结合亲和力。我们期望有天生的人的mabs 恢复将与较高的亲和力结合，并比出现慢性感染的人更具潜在的潜力。 我们还期望艾滋病毒会降低mAb的亲和力和效力。 该项目的创新方面包括：1）大量事件HBV感染的独特队列 自然恢复和病毒持久性都发生在有和没有的前瞻性追随者中 HIV感染，2）使用HEPG2-NTCP检测人类受试者血浆中NAB反应的能力 感染模型系统，以及3）分离HBV特异性B细胞进行离体研究的能力。迄今为止，这样 研究无法解释为什么对获得HBV的NAB响应的信息很少 直接来自感染的人类。该提案的结果将有助于我们理解影响 艾滋病毒对乙型肝炎的免疫反应，并可能促进未来的研究以开发功能性治疗 对于乙型肝炎，这是全球肝硬化和肝细胞癌的主要原因。