These newly identified cellular partners considerably expand the number of host proteins being potentially involved at some point in the flavivirus life cycle. It is worth noting

that most of the cellular proteins TNF-alpha inhibitor identified here have not been previously reported in the literature as flavivirus host factors, including in the two recent genome-wide RNA interferences studies [15, 16] and a DENV2 bacterial two-hybrid screen [24]. This lack of redundancy, which is commonly reported for such large-scale studies, implicates that both RNAi and two-hybrid approaches are not exhaustive and that complementary experimental approaches are needed to construct a comprehensive scheme of virus-host interactions eventually [25]. Interestingly, the topological analysis of our flavivirus-human

protein-protein interaction network reveals that flaviSelleckchem VX-680 viruses interact with highly connected and central cellular proteins of the human interactome, as previously reported for the hepatitis C Virus (HCV) and the Epstein Barr Virus (EBV) [11, 12]. Our study also unravels numerous shared cellular targets between flaviviruses and the Human Immunodeficiency Virus (HIV), the Papilloma viruses and the Herpes viruses. This finding supports the idea that a large variety of viruses use common mechanisms to interfere with cell organisation. Besides providing a synthetic view of flavivirus-host interactions, our interactome study sheds new light on the pathogenesis PRI-724 cell line of flavivirus infections. In particular, the NS3 and NS5 viral proteins were found to interact with several cellular proteins involved in histone complexe formation and/or in the chromatin remodelling process namely CHD3, EVI1, SMARCB1, HTATIP, and KAT5. Similarly in a recent system biology study aimed at describing the mammalian transcriptional network in dendritic cells, Amit et al. proposed that the chromatin

modification may be a key event during dendritic cells immune response against pathogens [26]. Interestingly, dengue virus presents a high primary tropism toward cells of the phagocyte mononuclear system, namely dendritic cells of PJ34 HCl the skin (Langerhans cells), monocytes and macrophages. Thus, the fact that proteins belonging to the flavivirus replication complex directly target central components of histone complex might suggest that flaviviruses escape host defense by disrupting and/or subverting the control of chromatin organization within infected immune cells. Moreover, by interacting with the chromatin remodelling machinery, some flaviruses may take advantage of host cells’ replicative machinery to interfere with the host cellular homeostasis and/or to replicate their own genome as previously shown for SMARCB1 and retroviral genome replication [27].