HSV-1 genome decompaction plays an important role in viral DNA sensing by PML-NB intrinsic antiviral regulators

Abstract

Constituent proteins that reside within promyelocytic leukaemia nuclear bodies (PML-NBs) are known to play an important role in cellular restriction of herpesvirus gene expression as a component of the intrinsic antiviral immune response to DNA virus infection. However, the precise mechanism(s) of PML-NB genome detection, entrapment, and silencing remain unknown. We have recently reported a sensitive method of viral genome detection that enables the visualisation of infecting EdC (5-Ethynyl-2’-deoxycytidine) labelled HSV-1 genomes (HSV-1EdC). We report that ultraviolet light (UV) irradiation of HSV-1EdC virions inhibits the nuclear recognition of viral DNA (vDNA) by core PML-NB constituent proteins (PML, Sp100, and Daxx). This impairment of recruitment was independent of UV source, but dependent on dose and time course of UV irradiation that correlated with a loss in viral genome decompaction upon nuclear entry. Moreover, UV treatment promoted premature uncoating of viral genomes within the cytoplasm of infected cells in a dose-dependent manner. Our data highlights the importance of genome decompaction in PML-NB sensing of infecting viral genomes. Additionally, it uncovers a previously undescribed mechanism of action for the induction of innate immune defences during herpesvirus infection that have historically utilised UV inactivation to promote the activation of cellular pattern recognition receptors (PPRs) and induction of interferon stimulated gene (ISG) expression.