Species-specific gB ectodomain interactions and cytoplasmic domain stability regulate herpes simplex virus fusion

Herpes simplex virus type 1 (HSV-1) entry requires the coordinated interaction of gD, gH/gL, and gB. Both gH/gL and gB are conserved herpesvirus proteins that are required for viral replication and are key targets of neutralizing antibodies. Despite their importance, how these proteins interact to mediate herpesvirus entry into cells remains poorly understood. In this study, we examined gB function by creating chimeras that swapped distinct domains between HSV-1 and saimiriine herpesvirus 1 (SaHV-1) homologs. Using these chimeras, we demonstrate that a species-specific interaction occurs in the gB ectodomain. Additionally, we found that the HSV-1 cytoplasmic tail domain (CTD) is hyperfusogenic compared to SaHV-1, suggesting that different gB domains can compensate for one another to balance fusion. This study provides new insight into how gB is regulated to mediate virus entry at the right time and place.