Abstract
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.