The Life Cycle of the Vaccinia Virus Genome

Poxviruses, of which vaccinia virus is the prototype, are a large family of double-stranded DNA viruses that replicate exclusively in the cytoplasm of infected cells. This physical and genetic autonomy from the host cell nucleus necessitates that these viruses encode most, if not all, of the proteins required for replication in the cytoplasm. In this review, we follow the life of the viral genome through space and time to address some of the unique challenges that arise from replicating a 195-kb DNA genome in the cytoplasm. We focus on how the genome is released from the incoming virion and deposited into the cytoplasm; how the endoplasmic reticulum is reorganized to form a replication factory, thereby compartmentalizing and helping to protect the replicating genome from immune sensors; how the cellular milieu is tailored to support high-fidelity replication of the genome; and finally, how newly synthesized genomes are faithfully and specifically encapsidated into new virions.