Herpes simplex virus (HSV) is a highly successful human pathogen that deploys various immunomodulators to combat the host immune system. One such protein is ICP47 that inhibits antigen presentation to CD8+ T cells by binding to the transporter associated with antigen processing (TAP), blocking peptide transport and loading onto MHC I. While there is biochemical evidence showing that ICP47 blocks mouse TAP very poorly, in vivo studies suggests that this protein contributes to HSV neurovirulence in mice. We are reexamining this discrepancy using a new set of ICP47 null viruses. Mutant ICP47 viruses were constructed using CRISPR Cas-9 genome editing technology to make precise nucleotide changes that disrupt translation of functional ICP47. Viral pathogenesis, reactivation and spread were assessed in mice infected with wildtype or ICP47 null viruses on the flank. Virus titers were similar between wildtype and mutant virus in the skin and sensory ganglia at 4 and 6 days after infection, indicating that ICP47 deficiency did not alter viral replication or assist in rapid clearance of virus. Once latency was established, sensory ganglia from spinal levels T5 to L1 were cultured ex vivo and assessed for virus reactivation to reflect the spread of HSV. No substantial difference in spread across different spinal levels was noted between mice infected with wildtype or mutant virus. We are now using a unique assay that for the first time directly quantifies the impact of ICP47 on antigen presentation to examine human versus mouse differences. Our study using different strains of HSV and mice, an alternate infection model and unique assays for quantifying antigen presentation will help to bridge the current gap between biochemical and pathogenesis data available for ICP47. This in turn helps us understand the extent to which species differences between humans and mice may confound mouse models of HSV.