The role of host heterochromatin during egress of lytic Herpes Simplex Virus 1

Abstract

The nucleus of a human cell is a crowded molecular environment full of DNA, RNA, and proteins. Viruses that replicate in the nucleus have bountiful access to host cell resources but must contend with existing host chromatin for space to replicate, assemble progeny, and exit from the nucleus. HSV-1 is one such nuclear-replicating virus that expertly manipulates host chromatin to benefit progeny production. In my dissertation studies, I found that HSV-1 lytic infection induces formation of new heterochromatin on host genomes through upregulation and re-localization of macroH2A1 and H3K27me3, marks that are frequently associated with transcriptionally repressed chromatin. Newly formed viral capsids traverse this chromatin maze to reach the nuclear periphery and ultimately exit the cell. When I reduced peripheral heterochromatin in infected cells, I found that capsid escape, or egress, from the nuclear compartment is impaired. My data suggest that HSV-1 maximizes its egress by inducing changes in nuclear architecture to allow capsids increased access to the nuclear periphery. My work helps illuminate how humans respond to infection by revealing that pathogens use a diverse range of molecular tools within the cell to enhance their replication, even transcriptionally inert heterochromatin.