Herpes simplex virus 1 is a contagious human pathogen, which affects about 70% of the world population. After a productive infection phase on the skin/mucous membrane, a latency phase follows in the sensory ganglia, which is life-long. CD8 T cells and NKT cells play vital roles in both acute and latent herpes simplex virus 1 infections. Both these components of cell-mediated immunity are activated by antigen presentation through molecules like MHC-I and CD1d. HSV-1 has evolved to evade immune surveillance through mechanisms like latency and establishment of infection in the neurons. By transient and stable expression in mammalian cells, we found that US3 protein kinase and US3.5, its shorter transcript, significantly down-regulate MHC-I from the cell-surface and cause its degradation in the proteasome. Also, US3K220M is a loss of function mutant of this kinase and is not able to down-regulate MHC-I. These results reveal a new role for viral protein kinases in modulation of host antigen presentation. Further, through co-IP and Western blot analysis, we mapped the interaction of CD1d and HSV-1 glycoprotein B to their extracellular domains.