Herpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms.
An understanding of the molecular events that regulate entry of herpes simplex virus type 1 (HSV-1) into a latent infection of neurons and subsequent reactivation requires model systems. However, establishing a latent-like infection in cultured neurons is problematic as the release of any infectious virus can potentially superinfect the cultures. Here, we describe a new reporter virus, HSV-1 Stayput-GFP, that is defective for cell-to-cell spread. Use of this virus permits the establishment of a quiescent infection of neurons without the need for a viral DNA replication inhibitor. As such, Stayput-GFP provides a new model to study latency establishment and reactivation at the single neuron level. We demonstrate that reactivation involves an initial wave of viral gene expression consistent with the Phase I previously observed in primary neuron models where a viral DNA replication inhibitor is used during latency establishment. Phase I gene expression was dependent on the cell stress protein DLK but independent of histone demethylase activity and viral DNA replication. Progression into the later, Phase II wave of reactivation, characterized by detectable late viral protein synthesis and a requirement for histone demethylase activity, is also observed in the Stayput-GFP model system. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and occur when latent infections are established in the absence of a viral DNA replication inhibitor.
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