Interplay between nuclear stress responses and herpesvirus latency

SUMMARY Neurotrophic a-herpesvirus including herpes simplex virus-1 (HSV1) establish lifelong, latent (non-replicating) infections in sensory and sympathetic neurons. Recurring reactivation episodes triggered in response to physiological stress interrupt latency and allow virus reproduction, shedding and spread to new hosts. While it has long been known that HSV1 reactivation can be triggered by a perplexing variety of physiological and neurological stresses, the underlying molecular mechanisms have remained obscure. Recent studies using cultured primary neurons to model HSV1 latency and reactivation, allows us to build a detailed but still incomplete picture of how the virus is maintained in a dormant state and how stress response pathways converge to disrupt this control leading to reactivation. By applying cutting-edge single cell technologies to a well-defined primary neuron infection model, we have now identified neuronal factors that are rapidly mobilized in response to HSV1 reactivation and have the potential to block the virus replication program at a defined stage. The long-reaching goal of this project is to elucidate the molecular mechanisms responsible for this cell-intrinsic host response. We propose studies to identify the viral reactivation signature recognized by the host neuron and will determine why virus gene expression is selectively inhibited. Furthermore, our multifaceted approach will allow us to decipher the complex relationship between a viral parasite and its human host. By defining the molecular processes involved in regulating the behavior of latent virus we hope to gain a better understanding how neurons can be protected from a wide range of intrinsic and extrinsic insults.