Viral pathogens have evolved over millennia by adapting to a limited number of cellular mechanisms for cellular entry, replication, assembly and budding. While protein interaction networks exist for several model organisms, experimental host-virus protein interactions has been recently elucidated. This type of protein interactions between smallpox and humans can lead to the formation of a new system that points specific features of pathogenesis. However, the difficulty of performing this type of experiments using variola. Detecting global insights on the convergently co-evolved protein domains between smallpox and humans proteins can point human gene receptors exploited by variola for replication, assembly and budding. Uncovering these relationships can allow the development of antivirals targeting specific viral genes or human receptors.