Poxviruses encode many immunomodulatory proteins that contribute to diseases such as smallpox and mpox. Among these poxviruses is vaccinia (VACV), which harbors a virulence factor (A35R) that is conserved among mammalian tropic poxviruses. Despite its role in virulence, limited information is available regarding the molecular mechanisms and role that A35R plays in increasing the pathogenicity of VACV. Previous studies indicate that A35R can inhibit major histocompatibility complex (MHC) class II antigen presentation. Additionally, we show that A35R has different effects on classical versus nonclassical MHC class I antigen presentation. In fact, current preliminary results show that A35R inhibits presentation by a non-classical MHC class Ib molecule but enhances presentation by a classical MHC class Ia molecule. Therefore, this project continues to investigate how A35R impacts MHC class I and II presentation and seeks to compare the homologous protein in ectromelia virus to identify a conserved mechanism of A35R function. 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.