Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site
Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site
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DOI：
10.1172/jci.insight.97018
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发表时间：
2018-03-08
期刊：
影响因子：
8
通讯作者：
Ackerman, Margaret E.
中科院分区：
文献类型：
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作者：
Cheng, Hao D.;Grimm, Sebastian K.;Ackerman, Margaret E.
在供体鉴定、抗原探针设计和克隆病原体特异性抗体的实验方法方面取得的重大进展，导致新发现的识别HIV-1包膜糖蛋白的广泛中和抗体（bnAbs）数量呈指数增长。这些bnAbs的特性定义了新的表位和新的识别模式，可以导致HIV-1的有效中和。然而，将生物物理分析中的包膜识别谱转化为体内活性的理解已经落后，并且具有有效抗病毒活性的受试者和单克隆抗体的鉴定仍然依赖于对中和效力和广度的经验评估。为了开始解决重组蛋白识别和病毒中和之间的差异，我们研究了一组CD4结合位点（CD4bs）抗体的精细表位特异性，以确定针对CD4结合的HIV-1包膜位点的功能性有效体液应答的分子识别特征。虽然之前的研究使用中和数据和机器学习方法来提供表位图，但在这里，这种方法是相反的，表明简单的表位特异性结合试验可以前瞻性地识别广泛中和的cd4bs特异性单克隆抗体。基于这一结果，我们表明表位定位和中和广度预测也可以在多克隆血清反应评估中完成。因此，本研究鉴定了一组CD4bs bnAb特征氨基酸残基，并证明了对特征位置突变的敏感性足以预测多克隆血清的中和广度，具有跨群体和跨进化支的高度准确性。
Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs-specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades.