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Semin Liver Dis. 2000;20(1):57-68.

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

Author information

1
Department of Medicine, Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. ab8@doc.mssm.edu

Abstract

Hepatitis C virus (HCV) is a positive sense virus with a genomic RNA molecule 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 (coding region) in between. The 5'NTR and portions of the 3'NTR are the most conserved parts of HCV RNA. These conserved regions contain signals for replication and translation. Much of the 5'NTR is folded into a structure that binds ribosomes. This structure, an internal ribosome entry site, promotes the initiation of protein synthesis and is critical for HCV gene expression. The ribosome binding site may extend into the coding region; its exact boundaries are not known. The open reading frame encodes the HCV polyprotein, which is slightly more than 3,000 amino acids in length. The 3'NTR plays a key role in HCV replication and may also influence the rate of HCV protein synthesis. During replication, the genomic RNA is copied by virally encoded enzymes into a complementary antigenomic RNA, which itself is a template for the synthesis of progeny RNAs. At steady state, genomic strands outnumber 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 mixed population of RNA sequences (quasispecies), including mutants that may be more 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 time, mutation, selection, and population bottlenecks 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 innate 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 HCV RNA and allow the virus to escape specific immune responses. Antisense drugs 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 HCV-specific double-stranded RNA. Infectious clones of HCV RNA are available. These clones and other systems for expressing HCV proteins pave the way for vaccine development.

PMID:
10895432
[Indexed for MEDLINE]

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