Characterizing the broad antibody response to HIV superinfection

表征对 HIV 重复感染的广泛抗体反应

• 批准号: 10088378
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 80.24万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-07 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088378
• 关键词: Address; Affect; Affinity; Amino Acids; Antibodies; Antibody Response; Antibody Specificity; Antibody-mediated protection; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biochemical; Cell Lineage; Collection; Complex; Data; Development; Epitopes; Evolution; Growth; HIV; HIV Antibodies; HIV Infections; HIV antiretroviral; HIV vaccine; Human; Immune system; Individual; Infection; Lead; Maps; Methods; Monoclonal Antibodies; Mutation; Pathway interactions; Plasma; Play; Population; Process; Property; Recording of previous events; Research; Resistance; Role; Sampling; Specificity; Structure; Time; Variant; Viral; Virus; cohort; follow-up; insight; neutralizing antibody; novel; polyclonal antibody; progenitor; response; superinfection; vaccine response

ABSTRACT: Eliciting broad and potent HIV-specific neutralizing antibody (Nab) responses represents a holy grail of HIV vaccine efforts. To date, our understanding of the potential of the human immune system to generate such responses comes from the study of a subset of HIV-infected individuals who generate broad Nab responses as a result of a dominant monoclonal response. In contrast to the singly infected individuals who have been the topic of these previous studies, there is limited data on people who are superinfected with HIV and acquire two distinct strains of the virus from different partners. We have shown that superinfected individuals have broad Nab responses that cannot be explained by a monoclonal response to the known HIV epitopes. Our preliminary detailed study of one individual suggests that superinfection leads to a polyclonal response that results from distinct responses to the two infecting viral strains. We hypothesize that the complex dynamic between viruses in superinfection may contribute to the unique polyclonal response. To address this hypothesis, we propose to take advantage of our well-characterized cohort of superinfection, which represents the largest collection of cases identified to date. Among these individuals, we have identified several with broadly neutralizing antibody responses that do not map to a single known epitope target. We propose to isolate monoclonal antibodies from these individuals and determine the basis for the breadth of their response and whether the response is polyclonal. We will define the epitopes of the antibodies and the role that the initial and superinfecting virus played in eliciting them. We will also determine the evolutionary process that led to these responses. These studies represent a unique opportunity to understand how to elicit a polyclonal response to HIV, which may present a higher barrier to escape and resistance than a monoclonal response.

抽象的： 引发广泛而有效的 HIV 特异性中和抗体 (Nab) 反应是 HIV 的圣杯 疫苗工作。迄今为止，我们对人类免疫系统产生这种能力的潜力的了解 反应来自对 HIV 感染者子集的研究，这些人产生广泛的 Nab 反应，如 显性单克隆反应的结果。与单独感染者相比 关于这些先前研究的主题，关于双重感染艾滋病毒并获得两种病毒的人的数据有限 来自不同伙伴的不同病毒株。我们已经表明，重复感染者具有广泛的 Nab 反应无法用对已知 HIV 表位的单克隆反应来解释。我们的 对一个人的初步详细研究表明，重复感染会导致多克隆反应， 这是对两种感染病毒株的不同反应的结果。我们假设复杂的动态 重复感染中病毒之间的相互作用可能有助于独特的多克隆反应。为了解决这个问题 假设，我们建议利用我们特征明确的重复感染队列，它代表 迄今为止发现的最大的病例集合。在这些人中，我们确定了几位 广泛中和不映射到单个已知表位靶标的抗体反应。我们建议 从这些个体中分离单克隆抗体并确定其反应广度的基础 以及反应是否是多克隆的。我们将定义抗体的表位以及初始抗体的作用 重复感染病毒在引发这些症状方面发挥了作用。我们还将确定导致的进化过程 这些回应。这些研究提供了了解如何引发多克隆抗体的独特机会 对 HIV 的反应，与单克隆反应相比，这可能会带来更高的逃逸障碍和抵抗力。