Herpes Simplex Virus Glycoprotein C Regulates Low pH Entry

Abstract

AbstractHerpes simplex viruses (HSVs) cause significant morbidity and mortality in humans worldwide. Herpesviruses mediate entry by a multi-component, virus-encoded machinery. Herpesviruses enter cells by endosomal low pH and pH-neutral mechanisms in a cell-specific manner. HSV mediates cell entry via envelope glycoproteins gB, gD, and the heterodimer gH/gL regardless of pH or endocytosis requirements. HSV envelope proteins that function selectively in a given entry pathway have been elusive. Here we demonstrate that gC regulates cell entry and infection by a low pH pathway. Conformational changes in the core herpesviral fusogen gB are critical for membrane fusion. The presence of gC conferred a higher pH threshold to acid-induced antigenic changes in gB. Thus, gC may selectively facilitate low pH entry by regulating conformational changes in the fusion protein gB. We propose that gC modulates the HSV fusion machinery during entry into pathophysiologically relevant cells, such as human epidermal keratinocytes.ImportanceHerpesviruses are ubiquitous pathogens that cause lifelong latent infections and are characterized by multiple entry pathways. We propose that herpes simplex virus (HSV) gC plays a selective role in modulating HSV entry by a low pH pathway, such as into epithelial cells. gC facilitates conformational change of the main fusogen gB, a class III fusion protein. We propose a model whereby gC functions with gB, gD, and gH/gL to allow low pH entry. In the absence of gC, HSV entry occurs at a lower pH, coincident with trafficking to a lower pH compartment where gB changes occur at more acidic pHs. This study identifies a new function for gC and provides novel insight into the complex mechanism of HSV entry and fusion.