Hepatitis C virus RNA codes for proteins and replicates: Does it also trigger the interferon response?

Hepatitis C virus (HCV) is a positive sense virus with a genomic RNA molecu le roughly 9,600 nucleotides in length. The single-stranded genomic RNA has a nontranslated region (NTR) at each end and a long open reading frame (co ding region) in between. The 5 'NTR and portions of the 3'NTR ave the most conserved parts of HCV RNA. These conserved regions contain signals for rep lication and translation. Much of the 5 'NTR is folded into a structure tha t binds ribosomes. This structure, an internal ribosome entry site, promote s the initiation of protein synthesis and is critical for HCV gene expressi on. The ribosome binding sire may extend into the coding region; its exact boundaries are not known. The open reading frame encodes the HCV polyprotei n, which is slightly more than 3,000 amino acids in length. The 3 'NTR play s a key role in HCV replication and may also influence the rate of HCV prot ein synthesis. During replication, the genomic RNA is copied by virally enc oded enzymes into a complementary antigenomic RNA, which itself is a templa te for the synthesis of progeny RNAs. At steady state, genomic strands outn umber antigenomic strands about 10 to 1. HCV RNA replication is thought to take place in the cytoplasm and is an error-prone process. It generates a m ixed population of RNA sequences (quasispecies), including mutants that may be move fit than the parental type, less fit, or equally fit (but distinct ). Natural selection acts upon the progeny RNAs, causing the population to change and drift. Over rime, mutation, selection, and population bottleneck s led to the evolution of varied genotypes. The HCV replication complex is a potential source of double-stranded RNA, a powerful inducer of interferon . Thus, HCV-specific double-stranded RNA may trigger the first steps of inn ate immunity; however for unknown reasons, the immune system often fails to clear the infection. The plasticity of the HCV genome and the low level of HCV gene expression may counterbalance any immunostimulatory effects of HC V RNA and allow the virus to escape specific immune responses. Antisense dr ugs and ribozymes directed against HCV RNA are under investigation. Future interventions may include nucleic acid drugs (antisense and ribozymes) and smaller pharmaceuticals that bind to intricate structures in HCV RNA and HC V-specific double-stranded RNA. Infectious clones of HCV RNA are available. These clones and other systems for expressing HCV proteins pave the way fo r vaccine development.