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.

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， 本提案将研究急性乙型肝炎感染后或治疗引起的感染控制后发生的情况。 MACS-WIHS 联合队列研究中有 185 人（74 名 HIV+）在随访期间患有急性乙型肝炎 且其自发控制 (n=163) 或慢性感染 (n=22) 的结果先前已达到 我们还将研究另外 21 名在接受 HBV 治疗期间获得功能性治愈的参与者。 （治疗诱导的控制）第一个目标侧重于期间和之后 30 个月的血浆 NAb 反应。 自发控制感染或未感染 HIV 的人的急性 HBV 感染。 HIV 感染者 (PWH) 的 NAB 反应会比未感染 HIV 的人更弱且更不持久 NAB 反应的持久性降低可能导致 HBV 再激活的风险增加。 我们还将通过治疗控制感染来评估参与者的血浆 NAB。 寻求这些参与者将表现出与自发控制的参与者相似的高 NAB 滴度 在第二个目标中，我们将从 HBV 表面抗原 (HBsAg) 特异性 B 细胞中分离出来。 我们将比较急性感染期间或治疗诱导对照前后获得的标本。 急性肝炎自发控制者之间 HBsAg 特异性 B 细胞受体的分子特征 感染者、慢性乙型肝炎患者以及通过治疗控制感染的患者。 还确定了 HIV 对这些分子特征的影响。在第三个目标中，我们将克隆单克隆抗体。 来自这些 HBsAg 特异性 B 细胞的抗体 (mAb) 并确定 mAb 的功能特征。 预计来自急性感染自发控制者的单克隆抗体将以更高的亲和力结合 比那些发展为慢性感染的人更有效地中和，并且治疗后控制单克隆抗体- 诱导控制剂将比预控制单克隆抗体更有效，我们还预计 HIV 会降低 该项目的创新方面包括：1) 具有独特的队列。 大量乙型肝炎病毒感染事件在人们中自发控制或病毒持续存在 有或没有 HIV 感染，以及通过治疗控制 HBV 的罕见个体，2) 能力 检测人类受试者血浆中的 NAb 反应，以及 3) 分离 HBsAg 特异性 B 细胞的能力 迄今为止，此类研究尚不可能，这解释了为什么有关的信息很少。 该提案的结果将有助于我们了解 HBV 感染者的 NAB 反应。 HIV 对乙型肝炎免疫反应的影响，可能有助于开发功能性治愈方法 乙型肝炎是全世界肝硬化和肝细胞癌的主要原因。