Glycoprotein C Mutations Regulate the Plaque Size of Fusion-Defective Herpes Simplex Virus

Herpes simplex virus 1 (HSV-1) entry is mediated by a core fusion machinery comprised of glycoproteins gD, gH/gL, and gB. The contributions of additional viral glycoproteins to this process are not well defined. Glycoprotein C (gC) is known to function in cell attachment to heparan sulfate and immune evasion but is dispensable for viral entry under standard conditions. Here, we show that gC can act as a conditional accessory regulator of HSV-1 entry and fusion. Using serial passage of fusion-defective viruses, we demonstrate that mutations in gC are repeatedly selected and can partially compensate for defects in entry and fusion. These findings indicate that gC contributes to viral fusion under suboptimal conditions and highlight a role for this accessory glycoprotein in the adaptability of herpesvirus entry.