PML-NB-dependent type I interferon memory results in a restricted form of HSV latency

Abstract

Herpes simplex virus (HSV) establishes latent infection in long-lived neurons. 24 During initial infection, neurons are exposed to multiple inflammatory cytokines but the 25 effects of immune signaling on the nature of HSV latency is unknown. We show that 26 initial infection of primary murine neurons in the presence of type I interferon (IFN) 27 results in a form of latency that is restricted for reactivation. We also find that the 28 subnuclear condensates, promyelocytic leukemia-nuclear bodies (PML-NBs), are 29 absent from primary sympathetic and sensory neurons but form with type I IFN 30 treatment and persist even when IFN signaling resolves. HSV-1 genomes colocalize 31 with PML-NBs throughout a latent infection of neurons only when type I IFN is present 32 during initial infection. Depletion of PML prior to or following infection does not impact 33 the establishment latency; however, it does rescue the ability of HSV to reactivate from 34 IFN-treated neurons. This study demonstrates that viral genomes possess a memory of 35 the IFN response during de novo infection, which results in differential subnuclear 36 positioning and ultimately restricts the ability of genomes to reactivate.