©2018 by Heldwein Lab

Herpesviral Egress

During herpesvirus egress, nascent capsids traverse multiple membranes, eventually forming mature infectious virions that exit the cell. Although egress is a process used by many viruses, unlike most other viruses, herpesviruses bud twice: first, at the nuclear envelope and then at the cytoplasmic membranes. Herpesviruses are the only known animal viruses that bud at the nuclear envelope. This unusual nuclear budding allows the viral capsid to escape from the nucleus into the cytoplasm. Herpesviral capsids are assembled in the nucleus but are too large to exit the nucleus through the nuclear pores. So, instead, they bud at the inner nuclear membrane (INM) forming perinuclear viral particles that pinch off into the perinuclear space (a process termed primary envelopment) and subsequently fuse with the outer nuclear membrane (ONM) (a process termed de-envelopment). The resulting cytoplasmic capsids bud again at the membranes derived from the trans-Golgi network (a process termed secondary envelopment), which generates mature virions that exit the cell by exocytosis. Egress is orchestrated by a complex network of protein-protein interactions. Although key participants have been identified, the knowledge of their specific roles and mechanisms is lacking. We will elucidate the structure-based mechanisms of nuclear budding, de-envelopment, and cytoplasmic budding by using a combination of structural biology, biochemistry, in-vitro reconstitution, and single-particle tracking assays. Our long-term goals are to elucidate the egress mechanisms at atomic-level detail and apply this knowledge to antiviral drug design.

Image from Bigalke et al., Annu Rev Virol (2016)