MOLECULAR VIROLOGY OF HEPATITIS-C VIRUS - AN UPDATE WITH RESPECT TO POTENTIAL ANTIVIRAL TARGETS

Hepatitis C virus (HCV), a positive-strand enveloped RNA virus, is a m ajor cause of chronic liver disease worldwide. Cis-acting RNA elements and virus-encoded polypeptides required for HCV replication represent attractive targets for the development of antiviral therapies. Intern al ribosome entry site-directed translation of HCV genome RNA produces a long polyprotein which is co- and post-translationally processed to yield at least 10 viral proteins. A host signal peptidase is responsi ble for maturation of the structural proteins located in the N-termina l one-third of the polyprotein. Thus far, four enzymatic activities en coded by the non-structural (NS) proteins have been reported. The NS2- 3 region encodes an autoproteinase responsible for cleavage at the 2/3 site. The N-terminal one-third of NS3 functions as the catalytic subu nit of a serine proteinase which cleaves at the 3/4A, 4A/4B, 4B/5A and 5A/5B sites, and NS4A is an essential cofactor for some of these clea vages. NS3 also encodes an RNA-stimulated NTPase/RNA helicase at its C terminus, and NS5B has been shown to possess an RNA-dependent RNA pol ymerase activity. To date, no functions have been reported for NS4B or NS5A in RNA replication, however, NS5A has been implicated in modulat ing the sensitivity of HCV to interferon. Sequence and structural cons ervation within the 3' terminal 98 bases of genomic RNA suggest a func tional importance in the virus life-cycle and hence another target for antiviral intervention, Recently, HCV infection was shown to be initi ated in chimpanzees following intrahepatic inoculation of RNA transcri bed from cloned HCV cDNA. The ability to generate large quantities of infectious HCV RNA may facilitate the development of reliable cell cul ture replication systems useful for the evaluation of antiviral drugs.