Interferon Dependent Immune Memory during HSV-1 Neuronal Latency Results in Increased H3K9me3 and Restriction of Reactivation by ATRX

Herpes simplex virus-1 (HSV-1) establishes a lifelong latent infection in neurons and reactivation from this latent state is the cause of recurrent oral and ocular infections, herpes simplex keratitis, and encephalitis. Neuronal conditions during initial HSV-1 infection have a long-term impact on latency, modulating how responsive latent genomes are to reactivation and, therefore, their ability to cause disease. Type I interferon (IFN) exposure during initial infection results in promyelocytic leukemia nuclear-body (PML-NB) formation and a more restrictive form of HSV-1 latency. Here we demonstrate that IFN induced PML-NBs recruit histone chaperones to the viral genome and promote the deposition of the repressive heterochromatin mark, histone H3 lysine 9 tri-methylation (H3K9me3), and its reader, ATRX (alpha-thalassemia/mental retardation, X-linked). This work reveals the mechanism by which immune signaling during initial infection induces an epigenetic memory on HSV-1 genomes that is maintained during latency and inhibits reactivation. ATRX is highly abundant in neurons and is essential for maintaining cellular heterochromatin during neuronal stress. Here we find that ATRX prevents transcription, and subsequent reactivation, from H3K9me3-bound latent genomes by remaining associated with viral chromatin following stress-induced phosphorylation of histone H3. This indicates that H3K9me3-associated viral genomes are refractory to reactivation when read by ATRX. This work demonstrates that ATRX acts as a neuronal restriction factor against HSV-1 reactivation, elucidating a new potential target for inhibiting HSV-1 reactivation and subsequent human disease.