Rapid glycoprotein evolution enables variant interactions in herpes simplex virus type 1

Glycoproteins cover the surface of enveloped viruses such as herpes simplex virus 1 (HSV-1). Whilst essential for cellular attachment and entry, they also are excellent targets for host immune responses. This dichotomy culminates in an evolutionary struggle in which receptor recognition and immune escape are intricately balanced. Herpesviruses feature a variety of different glycoproteins with diverse molecular functions. Here, we describe the rapid evolution of HSV-1 towards syncytial plaque phenotypes in Vero cell culture, as well as anti-gD antibody resistance in human foreskin fibroblast cells. Using a mild hypermutator virus to accelerate experimental evolution, we identified multiple genetic variants leading to syncytial plaques. Strikingly, these variants differentially affect interactions within viral populations. Whilst gK mutants engage in collective syncytia formation upon entry, accelerate superinfection exclusion and maintain fitness advantages at high multiplicities of infection, gB and gD mutants do not. Furthermore, we find gE mutants which lead to mouse anti-gD antibody resistance and cross protect wt virus in mixed populations. Our findings suggest complex social interactions within herpesvirus populations and illustrate the evolutionary plasticity and diverse function of their glycoproteins.