Hepatitis C virus: molecular biology and genetic variability.

The pathogenetic mechanisms of hepatitis C virus (HCV) infection are poorly known. An understanding of HCV biology and the potential clinical impact of HCV genetic variability is essential to managing, treating, and preventing HCV infections. HCV is a member of the Flaviviridae viral family. Its genome is a positive, single-strand RNA molecule. The structure of the HCV particles is poorly known due to the lack of an efficient cell culture system as well as a striking heterogeneity in density. The core protein may have a regulatory role on both viral and cellular gene expression. The mechanisms of HCV-RNA replication may include synthesis of negative strand intermediates, which drive synthesis of new positive RNA genomes. New procedures have been developed to better identify and characterize the HCV-RNA genome. The mechanisms of HCV persistence are currently unknown, although it is known that HCV chronicity develops despite humoral and cellular responses to HCV proteins. HCV-RNA shows significant genetic variability with an estimated rate of nucleotide change of approximately 10(-3) substitutions/site/year. Currently, three major HCV genotypes and three to seven minor subtypes can be distinguished. The geographical distribution of these genotypes and subtypes varies significantly. It appears that poor clinical response to interferon (IFN) is more common with HCV genotype 1. In addition, some studies have shown an association between chronic infection, severe chronic hepatitis, and cirrhosis with subtype 1b. Further, there is evidence for a potential direct effect of HCV in liver carcinogenesis, with subtype 1b possibly being an independent risk factor for hepatic carcinoma development. HCV-RNA circulates as a population of RNA molecules, which creates a heterogeneity referred to as "quasispecies." It is possible that some HCV strains might have direct clinical implications. It may be that highly heterogeneous populations observed prior to treatment might correlate with a lower rate of response to IFN therapy.