Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Nat Commun. 2024 Oct 12;15(1):8831. doi: 10.1038/s41467-024-53082-y.
Paramyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs.
副黏病毒包括麻疹、尼帕和副流感病毒，它们具有大流行潜力，是公共卫生威胁。人类副流感病毒 3 型（HPIV3）是儿科、老年和免疫功能低下人群发病的主要原因。目前尚无针对 HPIV3 的批准疫苗或疗法。针对病毒融合的中和单克隆抗体（mAbs）是减轻副黏病毒感染的一种潜在策略，但由于病毒进化导致的耐药性，其应用可能受到限制。副黏病毒通过与细胞膜融合进入细胞，该过程由一个由受体结合蛋白（HN）和融合蛋白（F）组成的复合物介导。现有的原子分辨率结构无法揭示病毒进入过程中的生理相关相互作用。我们展示了对一种抗 HPIV3 F 中和 mAb 产生耐药性的病毒粒子表面上的预融合 HN-F 复合物的冷冻电镜结构。F 中的单个突变会使 mAb 结合和中和作用丧失。在这些复合物中，通常抑制 F 触发的 HN 蛋白已转移以揭开 F 顶点的盖子。这些复合物更容易被触发融合。这些结构揭示了预融合 HN-F 复合物的适应性以及副黏病毒对 mAbs 的耐药机制，并有助于确定设计 mAbs 的潜在耐药障碍。
