Poxviruses infect a wide variety of animals, facilitated by an extensive set of immunomodulatory proteins. Of importance, the orthopoxvirus genus poses a threat to human populations via zoonotic transmission (e.g. mpox), and many of the immunomodulatory proteins in orthopoxviruses are incompletely described. One of these proteins is A35R, and despite early work identifying A35R as a virulence factor, limited information is available regarding the intricate functions and role that it plays in increasing pathogenicity. Therefore, this project continues to investigate how A35R impacts major histocompatibility complex (MHC) class I and II presentations and seeks to compare the homologous protein in ectromelia virus to understand the conserved mechanism that A35R induces. A comprehensive understanding of the pathways through which VACV modulates our immune system can guide further development of attenuated and/or non-replicating VACV strains, thus advancing current vaccines and treatments.