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The genomic RNA of hepatitis C virus encodes the viral polyprotein precursor that undergoes proteolytic cleavage into structural and nonstructural proteins by cellular and the viral NS2-3 and NS3 proteases.The NS3 protease is responsible for the cleavage downstream of NS3 in which NS4A protein functions as a cofactor.We have recently demonstrated an internal NS3 cleavage activity occurred in the presence of NS4A,both in culture cells and with a mouse model system.The internal cleavage requires the polyprotein processing activity of NS3 protease that can be supplemented in trans.Nevertheless,several mutations in NS4A disrupted the internal NS3 cleavage but did not affect polyprotein processing,indicating that NS4A contributes differently to these two proteolytic activities.The internal cleavage enhances the transforming activity of NS3 protein,but has only a slight effect on the viral replication.The multiple roles of NS4A in viral multiplication and pathogenesis make NS4A an ideal target for hepatitis C therapy.