Biochemical and immunologic properties of the nonstructural proteins of the hepatitis C virus: Implications for development of antiviral agents and vaccines

Infection with the hepatitis C virus (HCV) is the major cause of non-A, non -B hepatitis worldwide. The viral genome, a positive-sense, single-stranded 9.6-kb long RNA molecule, is translated into a single polyprotein of about 3,000 amino acids. The viral polyprotein is proteoytically processed to yi eld all the mature viral gene products. The genomic order of HCV has been d etermined to be C --> E1 --> E2 --> p7 --> NS2 --> NS3 --> NS4A --> NS4B -- > NSSA --> NS5B. C, E1, and E2 ave the virion structural proteins. Whereas the function of p7 is currently un known, NS2 to NS5B are thought to be the nonstructural proteins. Generation of the mature nonstructural proteins re lies on the activity of viral proteinases. Cleavage at the NS2-NS3 junction is accomplished by a metal-dependent autocatalytic proteinase encoded with in NS2 and the N-terminus of NS3. The remaining downstream cleavages are ef fected by a serine proteinase contained also within the N-terminal region o f NS3. NS3, in addition, contains an RNA helicase domain at its C-terminus. NS3 forms a heterodimeric complex with NS4A. The latter is a membrane prot ein that acts as a cofactor of the proteinase. Although no function has yet been attributed to NS4B, NSSA has been recently suggested to be involved i n mediating the resistance of the HCV to the action of inteferon. Finally, the NS5B protein has been shown to be the viral RNA-dependent RNA polymeras e. This article reviews the current understanding of the structure and the function of the various HCV nonstructural proteins with particular emphasis on their potential as targets for the development of novel antiviral agent s and vaccines.