Norris Michael J, Henderson Lauren A, Siddiquey Mohammed N A, Yin Jieyun, Yoo Kwangsun, Brunel Simon, Mor Michael, Saphire Erica Ollmann, Benedict Chris A, Kamil Jeremy P
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, USA.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Nat Microbiol. 2025 Jul;10(7):1605-1616. doi: 10.1038/s41564-025-02025-4. Epub 2025 Jun 30.
Human cytomegalovirus can cause severe birth defects upon infection in pregnant women and complications in immunocompromised patients. A major challenge for vaccine design is our incomplete understanding of the diverse protein complexes this virus uses to infect cells. In Herpesviridae, glycoproteins H and L (gH and gL) form complexes with other viral proteins that bind receptors to mediate cell-type-specific entry. Here we identify a distinct gH complex that is abundant on human cytomegalovirus virions and enhances infection of endothelial cells. In this complex, gH associates with UL116 and UL141 (an immunoevasin previously known to function intracellularly) but not with gL. We term this the gH-associated tropism and entry (GATE) complex and provide the cryo-electron microscopy structure at ~3.5 Å. The structure shows gH-only scaffolding, UL141-mediated dimerization and a heavily glycosylated UL116 cap. These findings identify a third virion surface complex that promotes cell entry and may represent a new target for vaccines or antiviral therapies.
人巨细胞病毒可在孕妇感染时导致严重的出生缺陷，并在免疫功能低下的患者中引发并发症。疫苗设计面临的一个主要挑战是，我们对这种病毒用于感染细胞的多种蛋白质复合物了解不全面。在疱疹病毒科中，糖蛋白H和L（gH和gL）与其他病毒蛋白形成复合物，这些复合物结合受体以介导细胞类型特异性进入。在这里，我们鉴定出一种独特的gH复合物，它在人巨细胞病毒病毒粒子上大量存在，并增强内皮细胞的感染。在这个复合物中，gH与UL116和UL141（一种以前已知在细胞内起作用的免疫逃避蛋白）结合，但不与gL结合。我们将其称为gH相关嗜性和进入（GATE）复合物，并提供了约3.5埃的冷冻电子显微镜结构。该结构显示仅gH的支架、UL141介导的二聚化以及高度糖基化的UL116帽。这些发现确定了第三种促进细胞进入的病毒粒子表面复合物，可能代表疫苗或抗病毒疗法的新靶点。
