The native conformational landscape and priming mechanism of herpes simplex virus glycoprotein B.

Abstract

Glycoprotein B (gB) of herpesviruses mediates membrane fusion with host cells during viral entry. Stabilizing gB in its prefusion conformation is a primary strategy for vaccine development. While prefusion-like gB structures of several human herpesviruses have been solved, the native conformational landscape and structural dynamics of gB remain largely unknown. Here, we report cryo-electron microscopy structures of herpes simplex virus type 1 (HSV-1) gB from virions, revealing a predominant prefusion state and a minor population of an intermediate, primed state. Unique to α-herpesviruses, a tethering helix cross-links adjacent protomers and stabilizes these conformations. A further downstream intermediate we named as the deep-primed state was captured in a mutant and showed that structural changes in the central helices drive the disengagement of the fusion loops from the membrane-proximal regions, priming gB for membrane insertion. Leveraging these structural insights, we engineered gB mutants locked in distinct conformational states. Our findings provide an atlas for designing gB-based vaccines more closely mimicking the infectious virus.