To further evaluate whether interactions between orthologous proteins are conserved we used co-immunoprecipitation to test 92 interactions predicted from 55 interactions detected in KSHV for the corresponding orthologs in HSV-1, mCMV and EBV. 11/19 (58%) of the predicted interactions could be confirmed by CoIP in HSV-1, 12/18 (67%) in mCMV and 36/55 (65%) in EBV, in comparison to 29/55 (53%) in KSHV itself ( Figures 5A and S9A and Table S9 ). The percentage of core-derived orthologs that were confirmed by CoIP significantly correlated with the number of species in which the interactions were detected in Y2H screens, suggesting that the accuracy increases with the number of positive assays ( Figure S9B , Table S10 ). As negative controls, ten interactions which were not detected in any of the Y2H screens were tested in four viruses (39 interactions in total, Table S10 ). Although the confirmation rate of these negative controls seems relatively high (6/39 (15%)), it is still significantly smaller than for the predicted interactions and correlates well with the confirmation rates of interactions observed in 2, 3 and 4 species ( Figure  S9B ). Due to the low coverage of the Y2H system many (particular weak) interactions were most likely missed, and the positively tested controls may be examples of such interactions. It also suggests that, although our core interactome is very dense, it has not yet reached full coverage. Since the confirmation rate by CoIP for the Y2H interactions in KSHV is not higher than for the predicted interactions in HSV-1, mCMV and EBV, we conclude that a high percentage of interactions between core orthologs are conserved despite low sequence similarity of some of the orthologs across subfamilies.