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

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， 关注HBV特异性中和抗体（NAB）、B细胞库和单克隆抗体， 急性B型肝炎感染后出现。该提案将在MACS-WIHS中研究185名男性（74名HIV阳性） 在随访期间患有急性B型肝炎且其结局为自然或非自然的患者的联合队列研究 先前确定了恢复（n=163）或病毒持久性（n=22）。第一个目标是比较 在急性乙型肝炎自然控制后30个月内， HBV感染与HIV感染者和非HIV感染者我们假设，在艾滋病毒感染者（PLWH）中， NAb的反应将比未感染HIV的人更弱和更不持久。耐久性降低 NAb应答的增加可能导致HIV感染后HBV再激活的风险增加。在第二 目的：我们将标记从参与者急性感染期间获得的标本中分离的HBV特异性B细胞 期然后，我们将确定和比较HBV特异性B细胞受体的分子特征， 自然恢复期和慢性B型肝炎之间的急性感染期。我们将 还确定HIV对这些分子特征和HBV特异性B细胞频率的影响。在 第三个目的，我们将从这些HBV特异性B细胞中克隆单克隆抗体（mAb），并确定其在HBV感染中的作用。 mAb的功能特征和结合亲和力。我们希望来自自然人的mAb 康复者将以更高的亲和力结合，并且比那些发展成慢性感染的人更有效地中和。 我们还预期HIV将降低mAb的亲和力和效力。 该项目的创新方面包括：1）大量HBV感染事件的独特队列 自然恢复和病毒持续存在都发生在前瞻性随访的人， HIV感染，2）使用HepG 2-NTCP检测来自人类受试者的血浆中的NAb应答的能力 感染模型系统，和3）分离HBV特异性B细胞用于离体研究的能力。迄今为止， 研究无法解释为什么获得的关于NAb对HBV应答的信息很少 直接从受感染的人身上这项提议的结果将有助于我们理解 HIV对B型肝炎免疫反应的影响，并可能促进未来的研究，以开发一种功能性治疗方法。 B型肝炎是全球肝硬化和肝细胞癌的主要原因。

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.