Davido Pilot Project Summary
The specific events that dictate herpes simplex virus type 1 (HSV-1)-cell interactions critically affect the outcome leading to either lytic or latent infection. An HSV-1 immediate-early (IE) regulatory protein that plays a key role in this process is infected cell protein 0 (ICP0). The ICP0 gene encodes a 775 amino acid (aa) protein that is a phosphorylated, nuclear E3 ubiquitin (Ub) ligase with the capacity to activate transcription of all classes of HSV-1 genes. ICP0 transactivates viral genes via its E3 ubiquitin ligase activity, ubiquitin being a post-translational modification typically associated with protein stability. As HSV-1 is an obligate intracellular pathogen that requires host factors to replicate, host cell factors are likely to play important roles in the ability of ICP0 to stimulate HSV gene expression. While insights as to how ICP0 and its interactions with cellular factors enhance HSV-1 replication has been primarily performed through cell biological and genetic based assays, a chemical biological approach using bioactives and natural compounds to understand ICP0 function and HSV-1 replication remain largely unstudied. Until potential inhibitors and pathways ICP0 interacts with are identified, it will be unclear as to the exact mechanisms ICP0 plays in the switch between the lytic and latent or quiescent phases of infection. Our long-term research goal is to elucidate the molecular interactions between HSV-1 and its host that modulate the HSV-1 life cycle and use this knowledge to ultimately develop therapeutic interventions for treating patients with HSV-1 diseases. The objective in this proposal is to initially identify novel mechanisms by which ICP0 stimulates viral gene expression to enhance HSV-1 productive infection using a chemical biology approach. Our central hypothesis is that inhibition of ICP0 function with small compounds will lead to the discovery of novel ICP0 interactions or pathways (with viral and/or cellular factors) that promote HSV-1 gene expression. Given the time frame of this pilot project grant, one specific aim is proposed: Specific Aim #1: Identify novel inhibitors of HSV-1 ICP0 and viral replication using chemical libraries that include compounds that recognize specific cellular targets/pathways.