Departments of 1Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 57599, USA.
J Infect Dis. 2010 Mar 15;201(6):946-55. doi: 10.1086/651022.
Severe acute respiratory syndrome (SARS) emerged as a human disease in 2002. Detailed phylogenetic analysis and epidemiologic studies have suggested that the SARS coronavirus (SARS-CoV) originated from animals. The spike (S) glycoprotein has been identified as a major target of protective immunity and contains 3 regions that are targeted by neutralizing antibodies in the S1 and S2 domains. We previously characterized a panel of neutralizing human monoclonal antibodies (MAbs), but the majority of epitopes recognized by the MAbs remain unknown.
In the present study, we generated neutralization escape mutants and studied the effect of these neutralization escape mutations on human and animal receptor usage as well as on in vitro and in vivo fitness.
Distinct but partially overlapping sets of amino acids were identified that are critical to the binding of MAbs with differential neutralization profiles. We also identified possible interactions between the S1 and S2 domains of the SARS-CoV S glycoprotein. Finally, we showed that escape from neutralization usually attenuates SARS-CoV infection.
These data provide a mechanism for overcoming neutralization escape by use of broadly cross-reactive cocktails of cross-neutralizing MAbs that recognize residues within the receptor-binding domain that are critical for virus replication and virulence.
严重急性呼吸系统综合症（SARS）于 2002 年出现人类疾病。详细的系统发生分析和流行病学研究表明，SARS 冠状病毒（SARS-CoV）来源于动物。刺突（S）糖蛋白已被确定为保护性免疫的主要靶标，包含 3 个被 S1 和 S2 结构域中中和抗体靶向的区域。我们之前对一组中和性人单克隆抗体（MAb）进行了表征，但 MAb 识别的大多数表位仍然未知。
在本研究中，我们生成了中和逃逸突变体，并研究了这些中和逃逸突变对人类和动物受体利用以及体外和体内适应性的影响。
确定了截然不同但部分重叠的氨基酸集，这些氨基酸对具有不同中和特性的 MAb 的结合至关重要。我们还鉴定了 SARS-CoV S 糖蛋白的 S1 和 S2 结构域之间可能的相互作用。最后，我们表明，中和逃逸通常会减弱 SARS-CoV 的感染。
这些数据提供了一种通过使用广泛交叉反应的中和性 MAb 鸡尾酒来克服中和逃逸的机制，这些 MAb 识别对病毒复制和毒力至关重要的受体结合域内的残基。
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