Characterizing the broad antibody response to HIV superinfection

摘要： 激发广泛而有效的HIV特异性中和抗体(NAB)反应是HIV的圣杯 疫苗努力。到目前为止，我们对人类免疫系统产生这种 反应来自对HIV感染者的子集的研究，这些人产生广泛的NAB反应，如 这是显性的单克隆性反应的结果。与那些单独感染的人相比， 这些先前研究的主题，关于重叠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。我们已经证明，重复感染的人有广泛的 NAB反应不能用对已知HIV表位的克隆反应来解释。我们的 对一个个体的初步详细研究表明，重叠感染会导致多克隆反应， 结果是对两种感染病毒株的不同反应。我们假设这个复杂的动态 病毒之间的重叠感染可能有助于产生独特的多克隆反应。要解决这个问题 假设，我们建议利用我们特征良好的重复感染队列，这代表了 迄今为止发现的最大规模的病例集合。在这些人中，我们发现有几个人 广泛中和不映射到单一已知表位靶点的抗体反应。我们建议 从这些个体中分离出单抗，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 而超级感染病毒在引诱它们的过程中发挥了作用。我们还将确定导致 这些回应。这些研究提供了一个独特的机会来理解如何诱导多克隆 对艾滋病毒的反应，它可能比单抗反应提供更高的逃脱和耐药性障碍。

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.