Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The GII.4 HuNoV causes most epidemics worldwide. This virus undergoes epochal evolution with periodic emergence of variants with new antigenic profiles and altered specificity for histo-blood group antigens (HBGA), the determinants of cell attachment and susceptibility, hampering the development of immunotherapeutics. Here, we show that a llama-derived nanobody M4 neutralizes multiple GII.4 variants with high potency in human intestinal enteroids. The crystal structure of M4 complexed with the protruding domain of the GII.4 capsid protein VP1 revealed a conserved epitope, away from the HBGA binding site, fully accessible only when VP1 transitions to a “raised” conformation in the capsid. Together with dynamic light scattering and electron microscopy of the GII.4 VLPs, our studies suggest a mechanism in which M4 accesses the epitope by altering the conformational dynamics of the capsid and triggering its disassembly to neutralize GII.4 infection.

由人类诺如病毒 (HuNoV) 引起的急性胃肠炎是一个重大的全球健康和经济负担，并且没有获得许可的疫苗或抗病毒药物。 GII.4 HuNoV 引起了全球大多数流行病。这种病毒经历了划时代的进化，定期出现具有新抗原特征的变体，并改变了对组织血型抗原（HBGA）的特异性，而HBGA是细胞附着和易感性的决定因素，阻碍了免疫治疗的发展。在这里，我们证明了源自美洲驼的纳米抗体 M4 在人类肠类中具有高效能中和多种 GII.4 变体。 M4 与 GII.4 衣壳蛋白 VP1 的突出结构域复合的晶体结构揭示了一个远离 HBGA 结合位点的保守表位，只有当 VP1 转变为衣壳中的“凸起”构象时，才能完全接近。结合 GII.4 VLP 的动态光散射和电子显微镜，我们的研究提出了一种机制，其中 M4 通过改变衣壳的构象动力学并触发其分解来中和 GII.4 感染来访问表位。