Neuronal latent infection of Herpes Simplex virus (HSV) is characterized by the association of the viral genome with repressive heterochromatin. Work for many groups has shown that histones associated with the latent genome have modifications indicative of different types of heterochromatin, including constitutive (H3K9me2/3) and facultative heterochromatin (H3K27me3). However, these subtypes of heterochromatin are largely understudied in terminally differentiated neurons. Further, hundreds of heterochromatin types exist, corresponding to different histone post-translational modifications and the reader proteins that bind them. Little is known about the histone reader proteins associated with the latent viral genome. A critical challenge in the field is neuronal heterogeneity, which likely drives divergent epigenetic outcomes and, consequently, varied reactivation potentials. Notably, the early host immune environment—specifically, exposure to type I or type II interferons during de novo infection—modulates the epigenetic structure of the viral genome and ultimately the reactivation capability. This indicates that neurons and the viral genome retain long-term molecular memory of prior immune stimulation, which ultimately determines reactivation potential. This talk will explore the role of specific heterochromatin-associated proteins in latency establishment, the different types of HSV-1 epigenetic structures that are more or less primed for reactivation, and how conditions during de novo infection, including exposure to interferons, have a long-term impact on the nature of HSV-1 latency and the ability of the virus to reactivate. Understanding the different types of heterochromatin that form on the latent genome is important for determining how latency is established and how heterochromatin is remodeled for reactivation. Ultimately, identifying epigenetic states that are less permissive to reactivation may facilitate the development of novel therapeutics to prevent reactivation.