Entry of Alphaherpesviruses

Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma membrane. This entry event is mediated by a set of essential entry glycoproteins, including glycoprotein D (gD), gHgL, and gB. gHgL and gB are conserved among herpesviruses, but gD is unique to the alphaherpesviruses and is not encoded by all alphaherpesviruses. gD is a receptor-binding protein, the heterodimer gHgL serves as a fusion regulator, and gB is a class III viral fusion protein. Sequential interactions among these glycoproteins are thought to trigger the virus to fuse at the right place and time. Structural studies of these glycoproteins from multiple alphaherpesviruses has enabled the design and interpretation of functional studies. The structures of gD in a receptor- bound and in an unliganded form reveal a conformational change in the C terminus of the gD ectodomain upon receptor binding that may serve as a signal for fusion. By mapping neutralizing antibodies to the gHgL structures and constructing interspecies chimeric forms of gHgL, interaction sites for both gD and gB on gHgL have been proposed. A comparison of the post fusion structure of gB and an alternative conformation of gB visualized using cryo- electron tomography suggests that gB undergoes substantial refolding to execute membrane fusion. Although these structures have provided excellent insights into the entry mechanism, many questions remain about how these viruses coordinate the interactions and conformational changes required for entry.