Respiratory Syncytial Virus-Neutralizing Monoclonal Antibodies Motavizumab and Palivizumab Inhibit Fusion
Respiratory Syncytial Virus-Neutralizing Monoclonal Antibodies Motavizumab and Palivizumab Inhibit Fusion
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DOI：
10.1128/jvi.02699-09
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发表时间：
2010-08-15
影响因子：
5.4
通讯作者：
Wu, Herren
中科院分区：
文献类型：
--
作者：
Huang, Kelly;Incognito, Len;Wu, Herren
呼吸道合胞病毒（RSV）是病毒引起的呼吸道疾病和婴儿住院的主要原因。帕利珠单抗是一种RSV中和单克隆抗体，临床上用于预防高危婴儿的严重RSV相关呼吸道疾病。莫他珠单抗是帕利珠单抗的一种亲和力优化形式，开发用于改善对RSV的保护。这些抗体结合RSV F蛋白，其在病毒附着中起作用并介导融合。确定这些抗体如何中和RSV对于帮助指导针对RSV和潜在的其他病毒的新抗体药物的开发是重要的。本研究旨在揭示帕利珠单抗和莫维珠单抗中和RSV的机制。开发了测定法以测试这些抗体在RSV复制期间的不同步骤中的作用。用帕利珠单抗或莫维珠单抗预处理病毒不抑制病毒附着或F蛋白与靶细胞膜相互作用的能力。然而，用这些抗体中的任一种预处理病毒导致不存在可检测的病毒转录。这些结果表明，帕利珠单抗和莫维珠单抗在F蛋白启动与细胞膜的相互作用之后和病毒转录之前的某个点起作用。帕利珠单抗和莫维珠单抗还抑制F蛋白介导的细胞间融合。因此，这些结果强烈表明这些抗体阻断细胞与细胞和病毒与细胞融合，因为这些过程可能是相似的。最后，帕利珠单抗和莫维珠单抗没有减少病毒出芽。基于从病毒融合蛋白的大量研究开发的模型，我们的结果表明，这些抗体可以防止融合过程所需的F蛋白的构象变化。
Respiratory syncytial virus (RSV) is a major cause of virus-induced respiratory disease and hospitalization in infants. Palivizumab, an RSV-neutralizing monoclonal antibody, is used clinically to prevent serious RSV-related respiratory disease in high-risk infants. Motavizumab, an affinity-optimized version of palivizumab, was developed to improve protection against RSV. These antibodies bind RSV F protein, which plays a role in virus attachment and mediates fusion. Determining how these antibodies neutralize RSV is important to help guide development of new antibody drugs against RSV and, potentially, other viruses. This study aims to uncover the mechanism(s) by which palivizumab and motavizumab neutralize RSV. Assays were developed to test the effects of these antibodies at distinct steps during RSV replication. Pretreatment of virus with palivizumab or motavizumab did not inhibit virus attachment or the ability of F protein to interact with the target cell membrane. However, pretreatment of virus with either of these antibodies resulted in the absence of detectable viral transcription. These results show that palivizumab and motavizumab act at a point after F protein initiates interaction with the cell membrane and before virus transcription. Palivizumab and motavizumab also inhibited F protein-mediated cell-to-cell fusion. Therefore, these results strongly suggest that these antibodies block both cell-to-cell and virus-to-cell fusion, since these processes are likely similar. Finally, palivizumab and motavizumab did not reduce viral budding. Based on models developed from numerous studies of viral fusion proteins, our results indicate that these antibodies may prevent conformational changes in F protein required for the fusion process.