呼吸道合胞病毒逃逸株对单克隆抗体预防的抗性比较

目的 Palivizumab（PZ）是目前临床使用的惟一一个预防人类感染性疾病的单克隆抗体，本研究评估不同逃逸株在棉鼠体内对PZ预防的抗件。方法在细胞培养系统中筛选获得PZ逃逸株，测定其全长F基因序列，用微量中和法评估逃逸株对PZ的抗性，在棉鼠模型体内观察逃逸株对PZ预防的抗性差异。结果筛选获得的PZ逃逸株于F蛋白内第268位氨基酸（F212）和272位氨基酸（MP4、MS312、MS412和MS512）发生替换。用Western blot检测发现所有逃逸株PZ识别位点抗原性改变。F212复制能力受损，而其他逃逸株复制能力与A2母株接近。与A2原型株比较，MP4和MS412在体内外对PZ的中和活性具完全抗性。F212体外对PZ中和活性显示不完全抗性，但大剂量PZ在棉鼠体内仍能有效预防F212感染。结论不同PZ逃逸株体内对PZ的预防效应可能具有不同程度的抗性，某些逃逸株即使在PZ筛选压力下产生，亦不一定导致临床后果。

Variable resistance to Palivizumab in cotton rats by respiratory syncytial virus escape mutants

Objective Palivizumab (PZ) is the only clinically available monoclonal antibody (McAb) in use against human infectious disease. This study was to evaluate differing resistance of escape mutants to PZ. Methods PZ resistant viruses were selected in cell culture, analyzed for F gene sequence and tested for susceptibility to PZ in cotton rats to further define the potential for RSV to resist prophylaxis. Results Mutant MS412 had an A to C mutation at nucleotide 827 in the F gene resulting in an amino acid change from Lys to Gln at position 272. Virus F212 had an A to T mutation at position 816 leading to an amino acid change from Asn to Ile at position 268. F212 had impaired growth kinetics in vitro . F212 was partially and MS412 was completely resistant to PZ neutralization in cell culture. A single prophylactic dose of 15 mg/kg PZ protected cotton rats from infection with F212 but not with MS412. Conclusion Individual RSV escape mutants of PZ varied in their susceptibility to PZ in vitro and in vivo . Mutations associated with PZ resistance do not necessarily result in failure of PZ prophylaxis.