Dual Impacts of a Glycan Shield on the Envelope Glycoprotein B of HSV-1: Evasion from Human Antibodies In Vivo and Neurovirulence

Identification of the mechanisms of viral evasion from human antibodies is crucial both for understanding viral pathogenesis and for designing effective vaccines. However, the in vivo efficacy of the mechanisms of viral evasion from human antibodies has not been well documented. Here we show in cell cultures that an N-glycan shield on the HSV-1 envelope glycoprotein B (gB) mediated evasion from neutralization and antibody-dependent cellular cytotoxicity due to pooled γ-globulins derived from human blood. We also demonstrated that the presence of human γ-globulins in mice and HSV-1 immunity induced by viral infection in mice significantly reduced the replication of a mutant virus lacking the glycosylation site in a peripheral organ but had little effect on the replication of its repaired virus. These results suggest that the glycan shield on the HSV-1 envelope gB mediated evasion from human antibodies in vivo and from HSV-1 immunity induced by viral infection in vivo. Notably, we also found that the glycan shield on HSV-1 gB was significant for HSV-1 neurovirulence and replication in the central nervous system (CNS) of naïve mice. Thus, we have identified a critical glycan shield on HSV-1 gB that has dual impacts, namely evasion from human antibodies in vivo and viral neurovirulence.IMPORTANCEHSV-1 establishes lifelong latent and recurrent infections in humans. To produce recurrent infections that contribute to transmission of the virus to new human host(s), the virus must be able to evade the antibodies persisting in latently infected individuals. Here we show that an N-glycan shield on the envelope glycoprotein B of HSV-1 mediates evasion from pooled γ-globulins derived from human blood both in cell cultures and mice. Notably, the N-glycan shield was also significant for HSV-1 neurovirulence in naïve mice. Considering the clinical features of HSV-1 infection, these results suggest that the glycan shield not only facilitates recurrent HSV-1 infections in latently infected humans by evading antibodies, but is also important for HSV-1 pathogenesis during the initial infection.