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

• Published in: EMBO reports Vol. 22; no. 9; pp. e52547 - n/a
• Main Authors: Suzich, Jon B, Cuddy, Sean R, Baidas, Hiam, Dochnal, Sara, Ke, Eugene, Schinlever, Austin R, Babnis, Aleksandra, Boutell, Chris, Cliffe, Anna R
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 06.09.2021; John Wiley and Sons Inc
• Subjects: Animals; Cytokines; Depletion; Genome, Viral; Genomes; Herpes simplex; Herpes Simplex - genetics; Herpesvirus 1, Human - genetics; HSV; Immunological memory; Infections; Inflammation; Interferon; Interferon Type I - genetics; Latency; Latent infection; Leukemia; Mice; neuron; Neurons; PML‐NB; Promyeloid leukemia; Sensory neurons; Signaling; Virus Latency; Viruses; neuron; HSV; interferon; PML-NB; latency
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202152547

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 are 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 find 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 colocalize with PML‐NBs throughout a latent infection of neurons only when type I IFN is present during initial infection. Depletion of PML prior to or following infection does not impact the establishment latency; however, it does 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 results in differential subnuclear positioning and ultimately restricts the ability of genomes to reactivate. Synopsis Latent HSV‐1 genomes in peripheral neurons possess a long‐term memory of the IFN response in primary infection. This memory is characterized by association of latent genomes with IFN‐induced PML‐NBs and ultimately restriction of viral reactivation. Primary sympathetic and sensory neurons do not have detectible PML‐NBs. PML‐ NBs form with type I IFN treatment and persist even following cessation of IFN signaling. HSV‐1 genomes become entrapped by PML‐NBs throughout latency only when type I IFN is present during initial infection. PML‐NBs are not required for latency, but latent genomes are more restricted for reactivation when they are entrapped. Latent HSV‐1 genomes in peripheral neurons possess a long‐term memory of the IFN response in primary infection. This memory is characterized by association of latent genomes with IFN‐induced PML‐NBs and ultimately restriction of viral reactivation.