Entry of Herpesviruses into Cells: The Enigma Variations

The entry of herpesviruses into their target cells is complex at many levels. Virus entry proceeds by a succession of interactions between viral envelope glycoproteins and molecules on the cell membrane. The process is divided into distinct steps: attachment to the cell surface, interaction with a specific entry receptor, internalization of the particle (optional and cell specific), and membrane fusion. Several viral envelope glycoproteins are involved in one or several of these steps. The most conserved entry glycoproteins in the herpesvirus family (gB, gH/gL) are involved in membrane fusion. Around this functional core, herpesviruses have a variety of receptor binding glycoproteins, which interact with cell surface proteins often from different families. This interaction activates and controls the actual fusion machinery. Interactions with cellular receptors and between viral glycoproteins have to be tightly coordinated and regulated to guarantee successful entry. Although additional entry receptors for herpesviruses continue to be identified, the molecular interactions between viral glycoproteins remain mostly enigmatic. This chapter will review our current understanding of the molecular interactions that occur during herpesvirus entry from attachment to fusion. Particular emphasis will be placed on structure-based representation of receptor binding as a trigger of fusion during herpes simplex virus entry.