Herpes Simplex Virus 1 Envelope Glycoprotein C Shields Glycoprotein D to Protect Virions from Entry-Blocking Antibodies

Abstract

AbstractHerpes simplex virus 1 (HSV-1) gD interaction with the host cell receptor nectin-1 triggers the membrane fusion cascade during viral entry. Potent neutralizing antibodies to gD prevent receptor-binding or prevent gD interaction with gH/gL critical for fusion. HSV has many strategies to evade host immune responses. We investigated the ability of virion envelope gC to protect envelope gD from antibody neutralization. HSV-1 lacking gC was more sensitive to neutralization by anti-gD monoclonal antibodies than a wild type rescuant virus. gD in the HSV-1 gC-null viral envelope had enhanced reactivity to anti-gD antibodies compared to wild type. HSV-1 ΔgC binding to the nectin-1 receptor was more readily inhibited by a neutralizing anti-gD monoclonal antibody. HSV-1 ΔgC was also more sensitive to inhibition by soluble nectin-1 receptor. The viral membrane protein composition of HSV-1 ΔgC was equivalent to that of wild type, suggesting that the lack of gC is responsible for the increased reactivity of gD-specific antibodies and the consequent increased susceptibility to neutralization by those antibodies. Together, the results suggest that gC in the HSV-1 envelope shields both receptor-binding domains and gH/gL-interacting domains of gD from neutralizing antibodies, facilitating HSV cell entry.ImportanceHSV-1 causes lifelong infections. There is no vaccine and no cure. Understanding HSV immune evasion strategies is an important goal. HSV-1 gC is a multi-functional envelope glycoprotein. This study suggests that virion gC physically shields neighboring gD from antibodies, including neutralizing monoclonal antibodies. This mechanism may allow HSV to escape immune detection, promoting HSV infection in the host.