Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants and the elderly, and yet there remains no effective treatment or vaccine. The surface of the virion is decorated with the fusion glycoprotein (RSV F) and the attachment glycoprotein (RSV G), which binds to CX3CR1 on human airway epithelial cells to mediate viral attachment and subsequent infection. RSV G is a major target of the humoral immune response, and antibodies that target the central conserved region of G have been shown to neutralize both subtypes of RSV and to protect against severe RSV disease in animal models. However, the molecular underpinnings for antibody recognition of this region have remained unknown. Therefore, we isolated two human antibodies directed against the central conserved region of RSV G and demonstrated that they neutralize RSV infection of human bronchial epithelial cell cultures in the absence of complement. Moreover, the antibodies protected cotton rats from severe RSV disease. Both antibodies bound with high affinity to a secreted form of RSV G as well as to a peptide corresponding to the unglycosylated central conserved region. High-resolution crystal structures of each antibody in complex with the G peptide revealed two distinct conformational epitopes that require proper folding of the cystine noose located in the C-terminal part of the central conserved region. Comparison of these structures with the structure of fractalkine (CX3CL1) alone or in complex with a viral homolog of CX3CR1 (US28) suggests that RSV G would bind to CX3CR1 in a mode that is distinct from that of fractalkine. Collectively, these results build on recent studies demonstrating the importance of RSV G in antibody-mediated protection from severe RSV disease, and the structural information presented here should guide the development of new vaccines and antibody-based therapies for RSV.

呼吸道合胞病毒（RSV）是婴儿和老年人严重下呼吸道感染的主要原因，但仍没有有效的治疗方法或疫苗。病毒体表面装饰有融合糖蛋白（RSV F）和附着糖蛋白（RSV G），后者与人气道上皮细胞上的CX3CR1结合，介导病毒附着和随后的感染。RSV G是体液免疫反应的主要靶标，在动物模型中，靶向G中心保守区的抗体已显示出中和RSV的两种亚型，并能抵抗严重的RSV疾病。然而，用于该区域的抗体识别的分子基础仍是未知的。所以，我们分离了两种针对RSV G中央保守区的人类抗体，并证明它们在没有补体的情况下中和了人类支气管上皮细胞培养物的RSV感染。此外，这些抗体可以保护棉鼠免受严重的RSV疾病的侵害。两种抗体都以高亲和力与分泌形式的RSV G以及与未糖基化的中央保守区相对应的肽结合。与G肽复合的每种抗体的高分辨率晶体结构揭示了两个不同的构象表位，这些表位需要适当折叠位于中央保守区C端部分的胱氨酸套索。将这些结构与单独或与CX3CR1的病毒同系物复合的fractalkine（CX3CL1）的结构（US28）进行比较表明，RSV G将以不同于fractalkine的方式结合CX3CR1。总而言之，这些结果建立在最近的研究之上，这些研究表明RSV G在抗体介导的预防严重RSV疾病的保护中的重要性，并且此处提供的结构信息应指导针对RSV的新疫苗和基于抗体的疗法的开发。