Once an individual is infected with herpes simplex virus (HSV), the virus establishes a latent infection in sensory neurons. Periodically, stimuli induce lytic reactivation that results in disease ranging from recurrent oral or genital lesions to severe ocular disease. Initiation of lytic infection as well as reactivation from latency depends upon the expression of the viral (IE) immediate early genes. These genes are controlled by complex multiprotein enhancer assemblies that consists of viral and cellular components. Studies are designed to identify critical components and investigate their interactions and their biochemical functions in order to provide insights into the mechanisms that mediate viral IE gene expression. The mammalian transcriptional coactivator HCF-1 is one of the essential factors involved in both the assembly of the viral IE enhancer complex and the activation of IE gene transcription. Studies address functions of this coactivator during the viral lytic cycle and elucidate complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. Previous studies have determined that HCF-1 (i) functions as a component of chromatin modification complexes that are essential for modulating the chromatin status of the viral IE genes upon initiation of lytic infection; (ii) interacts with transcriptional elongation factors to drive productive primary infection and viral reactivation from latency; and (iii) is subject to signal mediated nuclear transport in latently infected sensory neurons that correlated with viral reactivation. These data indicate that HCF-1 and its associated protein components, play multiple critical roles in the switch from latency to the initiation of reactivation. In fiscal year 2022, using two distinct approaches, specific depletion of HCF-1 in sensory neurons in vivo demonstrated that HCF-1 is required to promote viral reactivation, in part, by modulating the epigenetic state of the latent viral genome. In separate studies, (i) a histone methyltransferase was implicated in induction of viral IE gene expression and inhibition of this factor suppressed initiation of lytic infection and productive reactivation from latency; and (ii) an HCF-1 associated epigenetic complex was shown to be required to reduce specific repressive histone marks to promote viral gene expression in primary cell cultures and in a neuronal cell culture system.