PML-Dependent Memory of Type I Interferon Treatment Results in a Restricted Form of HSV Latency

Abstract

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

New model integrates innate responses, PML‐NB formation, epigenetic control and reactivation from latency

“…It has previously been reported that quiescent genomes exist in multiple states with respect to activation of viral genes and that there is a relatively large proportion of genomes in primary mouse trigeminal neurons that is not stringently repressed (Terry‐Allison et al , 2007). Suzich and co‐workers now show that HSV latency represents multiple states with respect to repression and the ability to reactivate, and they provide a model to explain this phenomenon (Fig 1) (Suzich et al , 2021). They suggest a scenario in which infection of a naïve sensory neuron can establish latency that is more reactivatible, possibly maintained in the latent state by the polycomb repressor complexes PRC1/PRC2 as previously described (reviewed in Watson et al , 2013).…”

“…Suzich et al (2021) now elegantly demonstrate that the latent HSV genome can exist in multiple states with respect to reactivation that are a function of the presence of PML‐NBs. PML‐NBs have been shown to result in the deposition of histone H3.3 modified on lysine 9 by trimethylation (H3K9me3), and in the absence of PML, there is a shift versus H3K27me3 (Delbarre et al , 2017).…”

“…In systems where PML‐NBs are prominent, repressed viral genomes have been found to contain H3K9me3 marks (Cohen et al , 2018). Interestingly, however, Suzich et al (2021) make the observation that PML‐NBs are absent from primary sympathetic and sensory neurons and that the addition of type I interferon (IFN) induces the formation of PML‐NBs. Viral genomes localize to the induced PML‐NBs and establish a latent state that is more restrictive for reactivation.…”

“…Under these conditions, the viral genome is encapsulated within PML‐NBs, which leads to deep repression of viral gene expression. According to the model presented in this paper (Suzich et al , 2021), viral genomes possess a memory of the IFN response during de novo infection, resulting in differential subnuclear positioning of the genomes and their entrapment within PML‐NBs. Viral genomes in this state are severely restricted for reactivation.…”

“…The data by Suzich et al (2021) raises the possibility that infected non‐neuronal cells or professional immune cells provide the source of IFN in the course of an in vivo infection that render uninfected neurons more refractory to productive infection, which results in a more restrictive form of latency. Remarkably, the PML‐NBs that are induced by IFN remain after IFN signalling has waned, providing a memory of reactivation restriction.…”