PROCESSING PATHWAYS OF THE HEPATITIS-C VIRUS PROTEINS

Hepatitis C virus (HCV) is the major etiological agent of posttransfus ion and community-acquired non-A, non-B hepatitis, It is an enveloped virus, grouped as a separate genus in the Flaviviridae family, The plu s-stranded RNA genome encodes a polyprotein of about 3000 amino acids with the structural proteins core, El and E2 residing in the amino ter minal quarter of the polyprotein and the nonstructural proteins NS2, N S3, NS4A, NS4B, NS5A and NS5B in the remainder, Maturation of the stru ctural proteins is mediated by host cell signalases located in the lum en of the endoplasmic reticulum and cleaving behind stretches of hydro phobic amino acids, At least two virally encoded proteinases are respo nsible for processing of the NS proteins: a zinc-dependent metalloprot einase encompassing the NS2 domain and the amino terminal portion of N S3, which is essential for cleavage at the NS2/3 junction; a serine-ty pe proteinase located in the amino terminal domain of NS3 is required for cleavage at all sites downstream of the NS3 carboxy terminus, Howe ver, although the NS3 domain contains proteolytic activity, with the e xception of the NS5A/5B junction cleavage only occurs in the presence of NS4A. This 54 amino acid long peptide can modulate the proteolytic activity of the enzyme in cis and in tr ans, probably by the formation of a stable NS3/NS4A complex, Modulation of the proteinase activity m ay be a way to regulate the expression and replication of the HCV geno me. (C) European Association for the Study of the Liver.