The role of neutralizing antibodies in natural and treatment-induced control of hepatitis B with and without HIV-1 co-infection

中和抗体在自然控制和治疗诱导控制有或没有 HIV-1 合并感染的乙型肝炎中的作用

• 批准号: 10618760
• 负责人: Justin Richard Bailey
• 金额: $ 34.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-24 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618760
• 关键词: Acute; Acute Hepatitis; Adult; Affect; Affinity; Aftercare; Antibodies; Antibody Response; Antibody Therapy; Antibody titer measurement; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Blood; Characteristics; Chronic; Chronic Hepatitis B; Cirrhosis; Cohort Studies; Data; Development; Epitopes; HIV; HIV Antibodies; HIV Infections; HIV Seronegativity; HIV-1; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Virus; Human; Immune response; Immunocompetent; Immunoglobulin Somatic Hypermutation; In Vitro; Individual; Infection Control; Knowledge; Measures; Molecular; Monoclonal Antibodies; Outcome; Participant; Persons; Plasma; Primary carcinoma of the liver cells; Risk; Role; Sampling; Sorting; Specimen; Surface Antigens; System; Techniques; Testing; Time; Translating; Viral; Virus Diseases; Visit; acute infection; chronic infection; co-infection; cohort; follow-up; human subject; innovation; neutralizing antibody; next generation sequencing; novel; novel strategies; response

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 (NAbs), B cell repertoires, and monoclonal antibodies that develop after acute hepatitis B infection or after treatment-induced control of infection. This proposal will study 185 persons (74 HIV+) in the MACS-WIHS Combined Cohort Study who had acute hepatitis B while in follow- up and whose outcome of either spontaneous control (n=163) or chronic infection (n=22) was previously determined. We will also study an additional 21 participants with functional cure while on HBV treatment (treatment-induced control). The first Aim focuses on plasma NAb responses during and 30 months after spontaneous control of acute HBV infection in persons with and without HIV infection. We hypothesize that in persons with HIV (PWH), 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. We will also assess plasma NAbs in participants with treatment-induced control of infection. We hypothesize that these participants will demonstrate high NAb titers similar to those with spontaneous control of acute infection. In the second Aim, we will isolate HBV surface antigen (HBsAg)-specific B cells from specimens obtained during acute infection or before and after treatment-induced control. We will compare the molecular features of HBsAg-specific B cell receptors between those with spontaneous control of acute infection, those who develop chronic hepatitis B, and those with treatment-induced control of infection. We will also determine the effects of HIV on these molecular features. In the third Aim, we will clone monoclonal antibodies (mAbs) from these HBsAg-specific B cells and determine the mAbs’ functional characteristics. We expect that the mAbs from persons with spontaneous control of acute infection will bind with higher affinity and neutralize more potently than those who develop chronic infection, and that post-control mAbs from treatment- induced controllers will be more potent than pre-control mAbs. We also expect that HIV will decrease the affinity and potency of anti-HBs mAbs. Innovative aspects of this project include: 1) The unique cohort with a large number of incident HBV infections with either spontaneous control or viral persistence in people living with and without HIV infection, as well as rare individuals with treatment-induced control of HBV, 2) The ability to detect NAb responses in plasma from human subjects, and 3) The ability to isolate HBsAg-specific B cells for ex vivo study. To date, such studies have not been possible, explaining why there is little information on NAb responses in HBV-infected humans. Results from this proposal will contribute to our understanding of the effects of HIV on the immune response to hepatitis B and could facilitate development of a functional cure for hepatitis B, the leading cause of cirrhosis and hepatocellular carcinoma worldwide.

总结 本提案旨在了解艾滋病毒对B型肝炎体液免疫反应的影响， 重点关注HBV特异性中和抗体（NAb）、B细胞库和单克隆抗体， 急性B型肝炎感染后或治疗诱导的感染控制后发生。该提案将研究 在MACS-WIHS联合队列研究中，185名患者（74名HIV+）在随访期间患有急性B型肝炎- 自发控制（n=163）或慢性感染（n=22）的结果， 测定我们还将研究另外21名在HBV治疗期间功能性治愈的参与者 （处理诱导的对照）。第一个目标侧重于期间和30个月后的血浆NAb反应 HIV感染者和非HIV感染者中急性HBV感染的自发控制。我们假设， 对于HIV感染者（PWH），NAb反应将比非HIV感染者更弱，更不持久。 感染NAb应答的持久性降低可能导致HBV再激活的风险增加， 艾滋病毒感染。我们还将评估治疗诱导感染控制的受试者的血浆NAb。我们 假设这些受试者将表现出与自发对照组相似的高NAb滴度 急性感染。在第二个目标中，我们将从人外周血中分离HBV表面抗原（HBsAg）特异性B细胞。 在急性感染期间或治疗诱导控制前后获得的标本。我们将比较 自发性急性脑梗死患者外周血淋巴细胞中HBsAg特异性B细胞受体的分子特征 感染者、慢性B型肝炎患者和经治疗控制感染者。我们将 还确定了艾滋病毒对这些分子特征的影响。在第三个目标中，我们将克隆单克隆 从这些HBsAg特异性B细胞中提取抗体（mAb）并确定mAb的功能特征。我们 预期来自自发控制急性感染的人的mAb将以更高的亲和力结合， 比那些发展成慢性感染的人更有效地中和，并且来自治疗的后对照mAb- 诱导的控制剂将比预控制单克隆抗体更有效。我们还预计，艾滋病毒将减少 抗-HBs mAb的亲和力和效力。该项目的创新方面包括：1）独特的队列， 大量的HBV感染事件，无论是自发控制还是生活在人群中的病毒持续存在， 有和没有HIV感染，以及治疗诱导控制HBV的罕见个体，2） 检测来自人类受试者的血浆中的NA B应答，和3）分离HBsAg特异性B细胞的能力 用于离体研究。到目前为止，这种研究还不可能，这解释了为什么关于 HBV感染者的NAb应答这项建议的结果将有助于我们了解 HIV对B型肝炎免疫反应的影响，并可能促进开发功能性治疗 B型肝炎是全世界肝硬化和肝细胞癌的主要原因。