Herpes simplex virus (HSV), a neurotrophic virus widespread among humans, is responsible for a variety of diseases, including life-threatening CNS infections, severe ocular disease, self-limiting epithelial sores in immunocompetent hosts, as well as disseminated disease in neonates and the immunocompromised. As a defining aspect of its pathogenesis, HSV establishes life-long latent infections in peripheral neurons where productive replication is suppressed. Periodically, latently-infected neurons reactivate in response to stress-related cues, including DNA damage, and initiate a lytic gene expression program that results in viral DNA synthesis and infectious virus production. While reactivation is associated with clinical and subclinical disease, little is known about the molecular mechanisms involved in latency and reactivation of the virus from primary neurons and the role of host DNA repair pathways in these processes. The long-term objective of this proposal is to understand how HSV pathogenesis in neurons is controlled by host DNA repair pathways. Based on our preliminary results, we hypothesize that the host DNA damage recognition and repair machinery regulates the balance between viral latency and lytic replication in peripheral neurons. To test this hypothesis we propose experiments to address: 1) How the herpesvirus life cycle and DNA repair pathways intersect to regulate herpesvirus lytic replication, and 2) How DNA repair choice regulates the latent-lytic switch in primary neurons. Understanding how host DNA repair pathways influence viral pathogenesis via their impact on growth, latency and reactivation will result in the identification of new targets for antiviral therapy and reveal new strategies for suppressing reactivation or eradicating latent genome reservoirs.
DNA repair pathways in human cells play an important role in preventing genomic instability, and can act as a barrier against developmental abnormalities and cancer. They can also be co-opted by viruses to enhance their own replication and growth and are responsible for many types of diseases in human. Understanding the molecular basis of how host DNA repair pathways impact latent and lytic viral infections has important long-term implications for health and disease.
