Found at: doi:10.1371/journal.pntd.0000446.s001 (0.05 MB PDF)  VirHostNet: a knowledge base for the management and the analysis of proteome-wide virus–host interaction networks Infectious diseases caused by viral agents kill millions of people every year. The improvement of prevention and treatment of viral infections and their associated diseases remains one of the main public health challenges. Towards this goal, deciphering virus–host molecular interactions opens new perspectives to understand the biology of infection and for the design of new antiviral strategies. Indeed, modelling of an infection network between viral and cellular proteins will provide a conceptual and analytic framework to efficiently formulate new biological hypothesis at the proteome scale and to rationalize drug discovery. Therefore, we present the first release of VirHostNet (Virus–Host Network), a public knowledge base specialized in the management and analysis of integrated virus–virus, virus–host and host–host interaction networks coupled to their functional annotations. VirHostNet integrates an extensive and original literature-curated dataset of virus–virus and virus–host interactions (2671 non-redundant interactions) representing more than 180 distinct viral species and one of the largest human interactome (10 672 proteins and 68 252 non-redundant interactions) reconstructed from publicly available data. The VirHostNet Web interface provides appropriate tools that allow efficient query and visualization of this infected cellular network. Public access to the VirHostNet knowledge-based system is available at http://pbildb1.univ-lyon1.fr/virhostnet. Eukaryotic cells express a large panel of proteins that coordinately participate to the cellular machinery through a highly connected and regulated network of protein-protein interactions (1) . Physical architecture of model organisms and human cellular protein networks exhibits a strong robustness against random failures, and strikingly a high sensitivity to targeted attacks on highly connected and central proteins, also called 'hubs' (2, 3) . Cellular protein network is not static and its robustness may change dynamically according to various factors like tissue and cell-line origins, signals received by cellular environment or more specifically during viral infections (4) . Replication and pathogenesis of viruses depend on a complex interplay between viral and host cellular proteins both acting through a complex network of protein-protein interactions. In order to evade the cell innate immune response and/or to favour their own replication and transmission, viruses have developed strategies to hijack central functions of the cell (5) (6) (7) . Viruses also use intra-viral, i.e. virus-virus, protein-protein interactions for virion assembly or viral egress from the cell. Accumulation of functional perturbations associated with such virus-virus and virus-host protein-protein interactions may lead to severe and complex diseases, like the development of cancers (8, 9) . From a systems biology perspective, a deeper understanding of infectious diseases may rely on an exhaustive characterization of all potential interactions occurring between proteins encoded by viruses and those expressed in infected cells (10) . Thus, integration of all protein-protein interactions into an infected cellular network, or 'infectome', is a great challenge that may provide a powerful framework for virtual modelling and analysis of viral infection.