THE NONSTRUCTURAL PROTEINS OF THE HEPATITIS-C VIRUS - STRUCTURE AND FUNCTIONS

The hepatitis C virus is the major causative agent of nonA-nonB hepati tis worldwide. Although this virus cannot be cultivated in cell cultur e, several of its features have been elucidated in the past few years. The viral genome is a single-stranded, 9.5kb long RNA molecule of pos itive polarity, The viral genome is translated into a single polyprote in of about 3000 amino acids. The virally encoded polyprotein undergoe s proteolytic processing by a combination of cellular and viral proteo lytic enzymes in order to yield all the mature viral gene products, Th e gene order of HCV has been determined to be C-E1-E2-p7-NS2-NS3-NS4A- NS4B-NS5A-NS5B. The mature structural proteins, C, E1 and E2 have been shown to arise from the viral polyprotein via proteolytic processing by host signal peptidases. Conversely, generation of the mature nonstr uctural proteins relies on the activity of viral proteases. Thus, clea vage at the NS2/NS3 junction is accomplished by a metal-dependent auto protease encoded within NS2 and the N-terminus of NS3. The remaining c leavages downstream from this site are effected by a serine protease c ontained within the N-terminal region of NS3. Besides the protease dom ain, NS3 also contains an RNA helicase domain at its C-terminus. NS3 f orms a heterodimeric complex with NS4A, The latter is a membrane prote in that has been shown to act as a cofactor of the protease. Whereas t he NS5B protein has been shown to be the viral RNA-dependent RNA polym erase, no function has yet been attributed to NS4B and NS5A, The latte r is a cytoplasmic phosphoprotein and appears to be involved in mediat ing the resistance of the hepatitis C virus to the action of interfero n.