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

摘要 这项建议旨在通过以下途径了解艾滋病毒对乙肝体液免疫应答的影响 重点关注乙肝病毒特异性中和抗体(NAB)、B细胞库和可 在急性乙肝感染后发生。这项建议将研究MACS-WIHS中的185名男性(74名HIV+) 联合队列研究谁在随访期间患有急性乙肝，他们的结果是 先前确定的是痊愈(n=163)或病毒持久性(n=22)。第一个目标是比较 急性肝炎自然控制后30个月抗-HBs-NAB反应的患病率和程度 艾滋病毒携带者和非艾滋病毒携带者中的乙肝病毒感染。我们假设在艾滋病毒携带者(PLWH)中， 与未感染艾滋病毒的人相比，NAB的反应将更弱、更难持久。耐用性降低 NAB反应的增加可能导致艾滋病毒感染后乙肝病毒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期间获得的样本中分离出的HBV特异性B细胞 句号。然后，我们将确定和比较乙肝病毒特异性B细胞受体的分子特征 自然恢复者和慢性乙肝患者之间的急性感染期。我们将 也要确定HIV对这些分子特征和对乙肝病毒特异性B细胞频率的影响。在……里面 第三个目标，我们将从这些乙肝病毒特异的B细胞中克隆出单抗，并确定 单抗的功能特性和结合亲和力。我们预计来自自然携带者的单抗 与慢性感染者相比，康复将以更高的亲和力结合，并更有效地中和。 我们还预计，HIV会降低单抗的亲和力和效力。 该项目的创新方面包括：1)大量事件乙肝病毒感染的独特队列 其中自然恢复和病毒持续存在都发生在预期跟踪的有无生活的人中 HIV感染，2)使用HepG2-NTCP检测受试者血浆中NAB反应的能力 感染模型系统，以及3)分离乙肝病毒特异性B细胞用于体外研究的能力。到目前为止，这样的 没有研究可以解释为什么关于NAB对乙肝病毒的反应的信息很少 直接来自受感染的人类。这项提议的结果将有助于我们了解影响 HIV对乙肝免疫反应的影响，并可能促进未来开发功能性治疗方法的研究 对于乙肝，这是全球肝硬变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.