Worldwide, HCV is a major etiologic agent of chronic hepatitis that may lead to the development of liver cirrhosis and hepatocellular carcinoma. Thus, significant morbidity and mortality is caused by HCV infection and effective control measures against the spread of this virus are needed. Originally, the extent of genetic heterogeneity of HCV was not fully appreciated. However, the breadth of the genetic heterogeneity of HCV is great, and this may have important implications in diagnosis, pathogenesis, treatment, and vaccine development. In an infected individual the HCV genome population circulates as a quasispecies distribution of closely related yet heterogeneous RNA sequences centered around one dominant sequence. The dominant sequence, as well as the consensus sequence, changes sequentially during the course of the infection. A hypervariable region (HVR1) within one of the envelope proteins of HCV (E2) evolves very rapidly. Patients infected with HCV mount a humoral immune response to epitopes of HVR1. However, sequential changes in the consensus sequence of HVR1 during infection result in the generation of variants that are not recognized by preexisting antibodies. This might represent a mechanism by which HCV evades host immune surveillance and establishes and maintains persistent infection. It will be important to determine whether HVR1 of HCV, as was found for the V3 loop of HIV, contains epitopes that elicit neutralizing antibodies against HCV. Furthermore, it will be important to determine whether the quasispecies nature of HCV helps the virus evade the cytotoxic T-cell response of the host. Analysis of complete or partial HCV genomic sequences revealed that HCV exists as multiple, distinct genotypes. A total of nine major genetic groups and at least 30 subgroups have been recognized. To evaluate the current classification of HCV genotypes, we performed phylogenetic analyses of complete and partial nucleotide sequences from isolates that represent all published variants of HCV. Analysis of complete HCV sequences, which represent three major genetic groups, supports the currently used genotype classification scheme. However, analysis of the partial genomic regions (ie, C, E1, and NS5b) of HCV isolates that represent all recognized variants of HCV demonstrates that the genetic relatedness among some of the genotypes was not equivalent in the different gene regions. Furthermore, the distinction among isolates, subtypes, and types of HCV was not always clear. This finding might reflect the shortcomings of analyzing only limited gene regions or may reflect the wide spectrum of genetic variation of HCV. Thus, it is important to determine the full-length sequence of representative HCV isolates of the different genotypes to resolve the ambiguities of classification resulting from analysis of partial sequences. Phylogenetic analysis of the C, E1, and partial NS5b gene sequences enabled us to determine the genotype of most published isolates of HCV. However, all other methods for determining the genotype of HCV isolates that do not require sequencing have obvious shortcomings. Thus, only sequence analysis of specific gene regions of the HCV genome that are predictive of genotype is completely reliable for genotyping. For the diagnosis of viral infection by methods for detecting HCV RNA it is essential to use probes/primers that are deduced from highly conserved domains within the 5' NC region of the HCV genome. The currently available HCV serological tests are sensitive for detecting HCV infection, and the important C22-3 protein of these tests is conserved among the different genotypes of HCV. Thus, in spite of the significant genetic heterogeneity of HCV, current diagnostic tests should be effective in detecting infection with the different genotypes of HCV. The sequence differences observed among the different HCV genotypes are very significant. The differences among the putative envelope proteins (eg, E1) of different HCV isolates are equivalent to that noted among the envelope proteins of members of different flavivirus subgenera and are greater than the variability observed among the envelope proteins of dengue viruses of different serotypes. Recent studies have suggested that the HCV genotypes are different with regard to pathogenesis and outcome of interferon therapy in HCV-infected individuals. The profound genetic heterogeneity of HCV is likely to make the development of a broadly effective vaccine difficult.
