[en] Replication of Hepatitis C virus (HCV) relies on multiple interactions with host factors but how these interactions determine infection, sensitivity to treatment and patho- genesis remain largely undefined. In a first attempt to provide a comprehensive view of a cellular infection by HCV, we present here a proteome-wide mapping of interactions between HCV and human cellular proteins. This interaction map was first generated by stringent high-throughput yeast two-hybrid (Y2H) screening, using both full-length HCV pro- teins and domains as baits. This map was then completed by an extensive mining of the literature. A total of 314 pairwise interactions between HCV and human proteins was identified by Y2H, and 170 by literature mining. The entire dataset was integrated into a reconstructed human interac- tome composed of 9,520 proteins and 44,223 interactions. The topological analysis of this network indicated that cel- lular proteins interacting with HCV are enriched in highly central and interconnected proteins, suggesting that HCV preferentially targets proteins with essential functions. A global analysis of these proteins based on functional anno- tation showed a highly significant enrichment for cellular pathways related to pathogenesis. A network comprising proteins associated to frequent clinical disorders of chron- ically infected patients was constructed by connecting the insulin, Jak/STAT and TGF-beta pathways with cellular pro- teins targeted by HCV. CORE protein appeared as a major perturbator of this network. The focal adhesion was also identified as a new function affected by the virus, mainly by NS3 and NS5A proteins.
