Our observations indicate that intraviral interactions between core proteins are conserved, and as a result we are not able to separate the Y2H interactomes into their phylogenetic subfamilies solely based on their core interactions. However, when interactions involving subfamily-specific proteins present in at least two of the virus species were included, we were able to generate a correct phylogenetic tree. This implies that interactions involving subfamily-specific proteins are at least partly conserved. Indeed, several of the interactions predicted from KSHV and confirmed in EBV by CoIP involved subfamily specific proteins. From published literature there are several examples of core interactions being conserved between species of different herpesviral subfamilies, e.g. the interactions between HSV-1 UL31 and UL34 [36, 37, 38, 39] , HSV-1 UL15 and UL28 [43, 44] and the HSV-1 UL54 self-interaction [45, 46] . Indeed, much of what is currently known about herpesvirus biology is derived from studies of Herpes Simplex Virus and extrapolated to other species. Our study indicates that it is effectively possible to transfer intraviral interactions between orthologous proteins from one species to another. Thus, by generating an overlay network from several genome-wide Y2H screens in related species, the large number of false negative interactions within each individual analysis can be overcome and a more complete picture of the core interaction network obtained.