The role of dicer and argonaute in HCV replication

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Our research focuses on how Hepatitis C virus replicates in human cells.  Because viruses are obligate intracellular parasites they must avoid cellular defense mechanisms and take over basic cellular operations in order to grow.  Thus studying how viruses replicate often reveals novel cellular processes.  We are interested in how the replication of HCV is influenced by host cell RNA interference (RNAi) activity.  Andrew Fire and Craig Mello first discovered RNAi in 1998 and were recently awarded a Nobel Prize for their work.  In plants, RNAi is an important antiviral defense mechanism in which single stranded viral genomic RNA is targeted for destruction by the presence of double stranded viral RNA intermediates.  In mammalian cells RNAi works quite differently.  Naturally occurring short double stranded RNAs, called microRNA activate similar machinery, but instead of targeting viral RNA for destruction they inhibit messenger RNA from being used for protein synthesis.  We are interested in the influence of RNA interference activity on the human virus Hepatitis C.  We disabled RNAi activity in cells and were surprised to find that virus replication decreased.  This suggested that instead of limiting virus replication as it does in plants, RNAi activity appears to benefit the replication of HCV.  Subsequent evidence suggests that this RNAi activity may be novel since it does not resemble other RNAi functions.  Our research program is designed to further our knowledge of this undefined cellular regulation mechanism and determine how HCV, a model virus of the Flaviviridae family of single stranded viruses uses this system for its own benefit.  In particular we will study the biochemical interactions between HCV and RNAi related proteins, and to find genetic links between HCV and RNA interference activity.   These studies will further our knowledge of cell regulation and virus replication and may reveal links between virus replication and pathogenesis.