Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the
histone H3.3 chaperone HIRA (
histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1)
infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated
Kinase (JAK),
Cyclin Dependent Kinase (CDK), and Sp100-dependent manner.
RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1
infection, including those involved in MHC-
I antigen presentation,
cytokine signalling, and
interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding
protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to
virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1
infection, respectively. These intracellular host defences are antagonized by the HSV-1
ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of
infection. Our study highlights the importance of
histone chaperones to regulate multiple phases of intracellular immunity to
virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.