Cell stress-mediated changes in the Herpes simplex virus type 1 chromatin structure during reactivation from latent infection

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Project Summary/abstract Herpes simplex virus (HSV) persists for life in peripheral neurons in the form of a latent infection. In response to neuronal stress, the virus reactivates from latency to permit reinfection. Reactivation is associated with significant disease. For example, replication in the cornea following reactivation results in keratitis. Transmission to the central nervous system following reactivation can result in herpes simplex encephalitis (HSE). Without treatment, HSE has a fatality rate of 70%, and even with treatment, many survivors exhibit long-term sequelae. Although anti-viral drugs are available that limit HSV productive replication, no therapies target the latent stage of infection to prevent reactivation and there is no vaccine against HSV. Therefore, our long-term goals are to understand how HSV responds to neuronal stress and develop strategies to prevent reactivation occurring. Our lab and others have shown that the mechanism by which viral gene expression initiates during reactivation is distinct from de novo infection with the virus. We have found that a neuronal stress pathway resulting in activation of c-Jun N-terminal kinase (JNK) triggers changes to the viral chromatin and permits reactivation. Specifically, the histones associated with viral promoters maintained a modification associated with heterochromatin (H3K9me3) but also became phosphorylated on H3S10 in a JNK-dependent manner. Using both a primary neuronal model of HSV-1 latency that we have developed and mouse models of infection we will determine how activation of JNK permits viral gene expression to be induced during reactivation. By performing ChIP-seq and shRNA knock-down of candidate proteins, we will examine how JNK gets recruited to viral promoters and identify additional cellular proteins involved in HSV-1 reactivation. We will also determine how JNK signaling overcomes the H3K27me3 repressive histone medication to permit reactivation from genomes associated with this modification. Finally, we will examine the mechanism that ATRX restricts HSV-1 reactivation and test the hypothesis that genomes associated with ATRX are non- permissive for reactivation. These studies into the intimate interaction between the latent viral genome and initiation of a neuronal stress response are especially significant as they provide mechanistic insight into how the virus undergoes reactivation. Because the virus has likely co-opted cellular pathway to achieve reactivation, we will also uncover process that are important for the host response to neuronal stress. Importantly, by understanding the very earliest events in HSV reactivation, our long-term goals are to develop therapies that target the latent genome and make it unresponsive for reactivation.