Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses
Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses
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DOI：
10.1073/pnas.0409065102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Nabel, GJ
中科院分区：
文献类型：
--
作者：
Yang, ZY;Werner, HC;Nabel, GJ
严重急性呼吸综合征冠状病毒的分子特征揭示了分离株之间的遗传多样性。刺突(S)糖蛋白是疫苗和免疫治疗的主要靶标，在其1255 -aa序列中出现了多达17个替换；然而，这些变化的生物学意义尚不清楚。在这里，通过分析S突变对病毒受体人血管紧张素转换酶2 （hACE-2）的亲和力，以及它们对病毒假型Ab中和的敏感性，确定了S突变的功能影响。虽然在2003年初人类暴发期间传播的8种菌株之间发现了微小的差异，但在2003年底广东省一个病例的S [S(GD03T0013)]和两只棕榈果子狸S（SZ3）和S（SZ16）中发现了重大的功能变化。S（GD03T0013）对hACE-2受体依赖性较小，对Ab抑制有明显抗性。出乎意料的是，中和大多数人S糖蛋白的抗体增强了果子狸病毒5糖蛋白介导的进入。增强的机制涉及抗体与hace -2结合域构象表位的相互作用。最后，改进的免疫原和单克隆抗体可以最大限度地减少这种并发症。这些数据表明，抗体可以增强严重急性呼吸综合征冠状病毒的进入，并强调需要针对这种新出现的病毒的不断变化的多样性进行疫苗和免疫疗法。
Molecular characterization of the severe acute respiratory syndrome coronavirus has revealed genetic diversity among isolates. The spike (S) glycoprotein, the major target for vaccine and immune therapy, shows up to 17 substitutions in its 1,255-aa sequence; however, the biologic significance of these changes is unknown. Here, the functional effects of S mutations have been determined by analyzing their affinity for a viral receptor, human angiotensin-converting enzyme 2 (hACE-2), and their sensitivity to Ab neutralization with viral pseudotypes. Although minor differences among eight strains transmitted during human outbreaks in early 2003 were found, substantial functional changes were detected in S derived from a case in late 2003 from Guangdong province [S(GD03T0013)] and from two palm civets, S(SZ3) and S(SZ16). S(GD03T0013) depended less on the hACE-2 receptor and was markedly resistant to Ab inhibition. Unexpectedly, Abs that neutralized most human S glycoproteins enhanced entry mediated by the civet virus 5 glycoproteins. The mechanism of enhancement involved the interaction of Abs with conformational epitopes in the hACE-2-binding domain. Finally, improved immunogens and mAbs that minimize this complication have been defined. These data show that the entry of severe acute respiratory syndrome coronaviruses can be enhanced by Abs, and they underscore the need to address the evolving diversity of this newly emerged virus for vaccines and immune therapies.