Sequence variability of hepatitis C virus and its clinical relevance.

Chronic type C hepatitis is a potentially serious disease that can lead to cirrhosis and hepatocellular carcinoma. This complex disease is caused by the hepatitis C virus (HCV), a positive sense, single-stranded RNA virus. HCV has been assigned to a separate genus within the Flaviviridae, and shares a close relationship to the pestiviruses. Nucleotide sequence variation has been observed in genomes amplified from serum of patients with HCV infection, and cloning of RNA amplified from patients infected with HCV has confirmed the heterogeneity of the agent responsible for post-transfusion and sporadic hepatitis C. The variability of HCV is structured in a way that immediately suggests a two tiered classification: this nomenclature comprises 'types' corresponding to the major branches in a phylogenetic tree of sequences from genomic or subgenomic regions of the genome, and 'subtypes', corresponding to the more closely related sequences within some of the major groups. This genotyping designation has provided an epidemiological tool for studying geographical differences in hepatitis C infection. Clearly discernible patterns of genotype distribution have been found in those countries that have been studied so far. In many European countries genotype distributions vary with the age of patients, reflecting rapid changes in genotype distribution with time within a single geographical area. Unfortunately we know very little about modes of transmission within different communities. There is considerable interest in the clinical significance of different HCV genotypes, and the intriguing question of whether these differences may affect the spectrum of the disease associated with hepatitis C. These data also have implications for diagnosis and treatment of acute and chronic hepatitis C. A uniform typing scheme and nomenclature will facilitate our understanding of the disease caused by this virus worldwide.