The invention features methods and compositions for screening for agents that modulate replication of a virus, particularly Flaviviridae virus (particularly hepatitis C virus (HCV)), where the methods provide for detection of agents that modulate the binding of TBC and NS5A, the inhibition of TBC activity, inhibition of Rab1 activity, and/or the expression of the TBC protein and/or Rab1 protein. The invention also features methods of controlling viral replication, and agents useful in such methods.