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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Epitope-focused immunogens against the CD4-binding site of HIV-1 envelope protein induce neutralizing antibodies against auto- and heterologous viruses
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Epitope-focused immunogens against the CD4-binding site of HIV-1 envelope protein induce neutralizing antibodies against auto- and heterologous viruses

机译：针对HIV-1包膜蛋白CD4结合位点的针对抗原决定簇的免疫原诱导针对自身和异源病毒的中和抗体

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Recent discoveries of broadly neutralizing antibodies (bnAbs) in HIV-1–infected individuals have led to the identification of several major “vulnerable sites” on the HIV-1 envelope (Env) glycoprotein. These sites have provided precise targets for HIV-1 vaccine development, but identifying and utilizing many of these targets remain technically challenging. Using a yeast surface display–based approach, we sought to identify epitope-focused antigenic domains (EADs) containing one of the “vulnerable sites,” the CD4-binding site (CD4bs), through screening and selection of a combinatorial antigen library of the HIV-1 envelope glycoprotein with the CD4bs bnAb VRC01. We isolated multiple EADs and found that their trimeric forms have biochemical and structural features that preferentially bind and activate B cells that express VRC01 in vitro. More importantly, these EADs could induce detectable levels of neutralizing antibodies against genetically related autologous and heterologous subtype B viruses in guinea pigs. Our results demonstrate that an epitope-focused approach involving a screen of a combinatorial antigen library is feasible. The EADs identified here represent a promising collection of possible targets in the rational design of HIV-1 vaccines and lay the foundation for harnessing the specific antigenicity of CD4bs for protective immunogenicity in vivo.
机译：最近在被HIV-1感染的个体中发现广泛中和抗体（bnAb）的发现已导致鉴定HIV-1包膜（Env）糖蛋白上的几个主要“易受感染部位”。这些场所为HIV-1疫苗的开发提供了精确的靶标，但是鉴定和利用其中许多靶标在技术上仍然存在挑战。通过基于酵母表面展示的方法，我们试图通过筛选和选择该抗原的组合抗原库，来鉴定包含“脆弱位点”之一的CD4结合位点（CD4bs）的针对抗原决定簇的抗原域（EAD）。 HIV-1包膜糖蛋白与CD4bs bnAb VRC01。我们分离了多个EAD，发现它们的三聚体形式具有生化和结构特征，可优先结合并激活在体外表达VRC01的B细胞。更重要的是，这些EAD可以在豚鼠中诱导出可检测水平的针对遗传相关自体和异源B型亚型病毒的中和抗体。我们的结果表明，涉及组合抗原库筛选的针对抗原决定簇的方法是可行的。此处鉴定的EAD代表了HIV-1疫苗合理设计中可能目标的有希望的集合，并为利用CD4bs的特异性抗原性提供了体内保护性免疫原性奠定了基础。

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