Relationship of herpes simplex virus genome configuration to productive and persistent infections

Infection of susceptible cells by herpes simplex virus (HSV) can lead to productive infection or to latency, where the genomes persist in the nuclei of peripheral neurons in a quiescent state. Using the HSV strain d109, which does not express any viral genes and thus establishes a quiescent state in most cells, we observed that a fraction of genomes circularized upon infection. The expression of infected cell protein (ICP) 0, which is known to be involved in reactivation from latency and the promotion of productive infection, inhibited the formation of circular genomes. Circular genomes were not observed upon infection of fully permissive cells by wild-type virus, in either the presence or absence of viral DNA replication. However, productive infection in the absence of ICP0 resulted in the accumulation of a subpopulation of circular genomes. The proportion of circular genomes formed during infection with an ICP0 mutant was greater at low multiplicity of infection, a condition in which ICP0 mutants replicate poorly. In the complete absence of viral gene expression, it was found that only circular genomes persisted in cells. These results suggest that circularization of the HSV genome may not occur early in the productive phase of wild-type HSV infection, but rather during establishment of a quiescent state or latency, providing a possible strategy for long-term persistence. Additionally, the circularization and possible fate of HSV genomes are regulated by an activity of ICP0.