Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design
Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design
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DOI：
10.1128/jvi.01546-17
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发表时间：
2018-01-01
影响因子：
5.4
通讯作者：
DuBois, Rebecca M.
中科院分区：
文献类型：
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作者：
Bogdanoff, Walter A.;Perez, Edmundo I.;DuBois, Rebecca M.
人类星状病毒被认为是全世界儿童、免疫功能低下患者和老年人病毒性腹泻的主要原因。目前尚无疫苗可预防星状病毒感染；然而，健康个体在先前感染期间产生的抗体与防止再次感染相关，这表明可以开发出有效的疫苗。在这项研究中，我们研究了几种人星状病毒血清型 2 (HAstV-2) 菌株对强效 HAstV-2 中和单克隆抗体 PL-2 (MAb PL-2) 具有抗性的分子机制。 HAstV-2 衣壳基因的测序揭示了衣壳刺突域内 PL-2 表位的突变。为了了解 MAb PL-2 中和抗性的分子基础，我们确定了这些 HAstV-2 菌株之一的衣壳刺突的 1.35-A 分辨率晶体结构。我们的结构揭示了由于丝氨酸到脯氨酸突变，PL-2 表位内的环发生了巨大的构象变化，将环锁定在空间上阻止 MAb PL-2 结合和中和的构象。我们证明丝氨酸突变允许环灵活性并恢复 MAb PL-2 结合。重要的是，我们发现该环中含有丝氨酸的 HAstV-2 衣壳刺突具有免疫原性，并引发中和所有 HAstV-2 毒株的抗体。总而言之，我们的结果对于合理选择抗原环中不含脯氨酸的疫苗株具有广泛的意义，从而引发针对不同环构象的抗体。 重要性 人类星状病毒 (HAstV) 在儿童时期感染世界上几乎每个人，并引起腹泻、呕吐和发烧。在这项研究中，我们研究了几种 HAstV 毒株如何对病毒中和单克隆抗体产生耐药性。我们确定了这些 HAstV 毒株之一的衣壳蛋白刺突结构域的晶体结构，并发现单个氨基酸突变会诱导负责抗体结合的环的结构变化。我们的研究结果揭示了病毒如何逃避抗体中和，并为疫苗的合理设计提供了见解，以引发多种抗体，从而提供更广泛的感染保护。
Human astroviruses are recognized as a leading cause of viral diarrhea worldwide in children, immunocompromised patients, and the elderly. There are currently no vaccines available to prevent astrovirus infection; however, antibodies developed by healthy individuals during previous infection correlate with protection from reinfection, suggesting that an effective vaccine could be developed. In this study, we investigated the molecular mechanism by which several strains of human astrovirus serotype 2 (HAstV-2) are resistant to the potent HAstV-2-neutralizing monoclonal antibody PL-2 (MAb PL-2). Sequencing of the HAstV-2 capsid genes reveals mutations in the PL-2 epitope within the capsid's spike domain. To understand the molecular basis for resistance from MAb PL-2 neutralization, we determined the 1.35-A-resolution crystal structure of the capsid spike from one of these HAstV-2 strains. Our structure reveals a dramatic conformational change in a loop within the PL-2 epitope due to a serine-to-proline mutation, locking the loop in a conformation that sterically blocks binding and neutralization by MAb PL-2. We show that mutation to serine permits loop flexibility and recovers MAb PL-2 binding. Importantly, we find that HAstV-2 capsid spike containing a serine in this loop is immunogenic and elicits antibodies that neutralize all HAstV-2 strains. Taken together, our results have broad implications for rational selection of vaccine strains that do not contain prolines in antigenic loops, so as to elicit antibodies against diverse loop conformations.IMPORTANCE Human astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. In this study, we investigated how several strains of HAstV are resistant to a virus-neutralizing monoclonal antibody. We determined the crystal structure of the capsid protein spike domain from one of these HAstV strains and found that a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.