Grant: Doctoral Research Award: Canada Graduate Scholarships

Herpes simplex virus (HSV) 1 and 2 are highly prevalent pathogens that collectively infect billions of people worldwide. HSV infectious particles ('virion') contain the virus's DNA genome within a protein shell capsid, a layer of viral and cellular proteins, and a viral envelope. These viruses form lifelong latent infections in sensory neurons wherein the virus can reactivate numerous times throughout the host's life and cause infection. Thus, research has focused on developing drugs that prevent HSV replication. HSV replicates in the nuclei of infected cells and must travel to the cytoplasm for the final stages of virion assembly. This process is regulated by the viral nuclear egress complex (NEC). The NEC is activated through a process called dephosphorylation, which is facilitated by cellular phosphatase 1 (PP1). When the NEC is activated, newly assembled genome-containing capsids transit through the nuclear envelope into the cytoplasm. An outstanding question in herpes virology is the mechanism by which the NEC is activated when a capsid is in proximity to the nuclear envelope. Our lab has found that PP1 is found on nuclear capsids, suggesting that PP1 may facilitate localized NEC dephosphorylation when capsids are in proximity. We will determine if PP1 on capsids activates the NEC through 2 steps: 1) by identifying which protein(s) are responsible for recruiting PP1 to the capsid, and 2) by introducing a mutation in this protein to prevent this interaction from occurring. If PP1 on capsids is necessary for this translocation, preventing PP1 from binding to capsids should prevent the translocation of capsids to the cytoplasm and abolish HSV replication. Understanding the role of PP1 in this conserved herpesvirus process may reveal new strategies for antiviral interventions. By impairing the recruitment of PP1 to capsids, capsid translocation to the cytoplasm and virion assembly will be inhibited, thereby preventing herpesvirus propagation.