Hepatitis C Reference Manual

Hepatitis C virus (HCV), identified in 1988 through molecular biological techniques, is an enveloped virus that has been classified as a separate genus in the Flaviviridae family. The HCV genome is a single-stranded, positive-sense ribonucleic acid (RNA) molecule approximately 9.5 kilobases in length. The genome consists of 5' and 3' noncoding regions encompassing a single open reading frame. The 5' noncoding region of the genome is followed by codes for structural proteins, including nucleocapsid (core) and two envelope glycoproteins (E1,E2). Codes for nonstructural proteins (NS2, NS3, NS4, NS5) extend to the 3' end.

Like other RNA viruses, the substantial heterogeneity of the HCV genome is the result of mutations that occur during viral replication. Within an infected individual, the genetic heterogeneity of HCV consists of a population of closely related yet heterogeneous sequences, called quasispecies, which result from the rapid development of mutations in a hypervariable region (HVR1) within one of the envelope proteins. Patients infected with HCV mount a humoral immune response to epitopes of HVR1, but sequential changes in the consensus sequence of HVR1 during infection result in variants that are not recognized by preexisting antibodies. The generation of these neutralization escape mutants appears to be the mechanism by which the virus establishes and maintains persistent infection. The lack of an effective neutralizing antibody response also means that natural infection does not protect against reinfection with the same or different genotypes of the virus.

Worldwide, six genetically distinct groups of HCV isolates, called genotypes, and a number of more closely related subtypes have developed as a result of accumulated mutations over time. The known genotypes have been numbered from 1 through 6, and the subtypes a, b, and c, in order of discovery. Studies in the United States on patients with chronic hepatitis C have shown that genotype 1 is the most common (about 70%) with 1a accounting for a slightly higher proportion than 1b. All genotypes are pathogenic, and there appears to be no correlation between genotype and source of infection. However, patients with HCV genotype 1a or 1b have lower rates of response to therapy than patients with other genotypes. The complexity of the infecting viral quasispecies in individual patients may also be an important factor related to treatment response.