Flaviviridae members are the causative agents of various diseases, such as yellow fever and West Nile encephalitis [3]. The NS5 protein of various Flaviviridae members has been demonstrated to provide a variety of roles, including but not limited to methyltransferase activity, RNA dependent RNA polymerase activity, and host immune response antagonism [1, 3, 5, 6, 8]. The mechanisms by which the RdRp region of NS5 alters pathogenicity of various Flaviviridae viruses has yet to be discovered. It is also unclear how this region of NS5 alters the IFN antagonism in the host, and if these two unknown factors interplay to cause the disease patterns present among Flaviviridae members. To further understand the complex mechanism that leads to differential pathogenicity of various Flaviviridae members, our research will focus on the determination of the effect(s) that NS5 RdRp activity has on the diverse…show more content… Recently, we have demonstrated that West Nile virus NS5 interacts with a novel cellular dispeptidase, prolidase, which ultimately inhibits IFNAR1 maturation and IFNAR1 levels [6]. This finding demonstrates that NS5 presents a new approach for understanding the complex interactions that lead to different pathology is Flaviviridae infections. It is understood that various NS proteins from this group of viruses play a role in host immune evasion and the blockade of these pathways, including NS3 and NS5 [1, 3, 5, 8]. These pathways are still unclear, and have not been extensively studied. Our work, however, demonstrates the first detailed study of the exact mechanism of a particular NS protein on IFN response, and how this alters viral differentiation. The significance of this research is in addressing how NS5 RdRp activity is altered among Flaviviridae members, leading to differential pathogenesis and disease burden via modulation of the host IFN immune response. We propose here that the RdRp activity of various Flaviviridae members allows for slight changes in NS5