Hepatitis C virus and the related bovine viral diarrhea virus considerably differ in the functional organization of the 5′ non-translated region: implications for the viral life cycle

The 5′ non-translated regions (5′NTRs) of hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV) initiate translation of the viral RNA genome through an internal ribosomal entry site (IRES) and operate as major determinants of the RNA replication cycle. We report on comparative studies with both virus systems demonstrating that the functional organization of the 5′NTRs of HCV and BVDV shows evident differences despite a similar RNA structure. In the BVDV 5′NTR, replication signals are restricted to the 5′ terminal domain I. With HCV, we defined specific replication signals in domain I but also in domains II and III that constitute the functional IRES. While the BVDV domain I supports IRES activity, the HCV domain I appears to down-regulate IRES function. These data suggest that HCV and BVDV apply different mechanisms to coordinate viral protein and RNA synthesis, which may explain differences in the replication efficiency of both related viruses.