The histone chaperone HIRA cooperates with PML-NBs to activate host innate immune defences in response to HSV-1 infection

Host innate immune defences play critical roles in restricting the propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) cooperates with promyelocytic leukaemia nuclear bodies (PML-NBs) to mediate the induction of innate immune defences in response to herpes simplex virus 1 (HSV-1) infection. Under conditions that activate innate immune signalling, HIRA relocalized from the nuclear matrix to PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA was required to promote the transcription induction of a broad repertoire of host genes implicated in the regulation of innate immunity to HSV-1 infection, including MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) products. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the efficient enrichment of HIRA directly onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immune defences to virus infection. Our data identifies independent roles for HIRA to mediate both the intrinsic repression of viral gene expression and induction of innate immune defences that restrict the initiation and propagation of HSV-1, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which mediates the disruption of PML-NBs from the outset of nuclear infection. Our study highlights the importance of histone chaperones to regulate multiple phases of host immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.