Characterizing the broad antibody response to HIV superinfection

摘要： 引发广泛而有效的HIV特异性中和抗体（Nab）反应代表了HIV的圣杯 疫苗的努力。到目前为止，我们对人类免疫系统产生这种免疫应答的潜力的理解， 这种反应来自对一部分HIV感染者的研究，这些人产生广泛的Nab反应， 这是显性单克隆反应的结果相比之下， 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个 来自不同伴侣的不同病毒株。我们已经证明，双重感染的个体具有广泛的 Nab应答不能用对已知HIV表位的单克隆应答来解释。我们 对一个个体的初步详细研究表明，重复感染导致多克隆应答， 这是由于对两种感染病毒株的不同反应。我们假设复杂的动力学 重叠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 假设，我们建议利用我们的良好特征的重复感染队列，这代表了 这是迄今为止发现的最大的一批病例。在这些人中，我们已经确定了几个与 广泛中和的抗体应答不映射到单一已知的表位靶标。我们建议 从这些个体中分离出单克隆抗体，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。 和重复感染的病毒在诱发它们中发挥了作用。我们还将确定导致 这些回应。这些研究代表了一个独特的机会，了解如何引起多克隆 对HIV的反应，这可能比单克隆反应提供更高的逃避和抵抗屏障。

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.