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The comprehensive yeast two-hybrid analysis of intraviral protein interactions in two members of the herpesvirus family, Kaposi sarcoma–associated herpesvirus (KSHV) and varicella-zoster virus (VZV), revealed 123 and 173 interactions, respectively. Viral protein interaction networks resemble single, highly coupled modules, whereas cellular networks are organized in separate functional submodules. Predicted and experimentally verified interactions between KSHV and human proteins were used to connect the viral interactome into a prototypical human interactome and to simulate infection. The analysis of the combined system showed that the viral network adopts cellular network features and that protein networks of herpesviruses and possibly other intracellular pathogens have distinguishing topologies.