INTRODUCTION — It became apparent after the discovery of the hepatitis A and B viruses in the late 1960s and early 1970s that a large proportion of cases of acute and chronic hepatitis could not be explained by either of these agents. Another viral agent was suspected, and patients infected with this suspected agent were said to have non-A, non-B hepatitis. The agent was finally identified in 1989 when the genome of the virus was cloned and the agent was designated the hepatitis C virus (HCV) [1].
HCV is closely related to flaviviruses and pestiviruses. Its genetic organization and protein products classify it in the Flaviviridae family, although its diversity is great enough for it to be classified as a separate genus. HCV is not related to any of the other known hepatitis viruses; however, the recently described hepatitis G virus is a distant relative. (See "GB virus C (hepatitis G) infection".)
VIRAL GENOME AND REPLICATION — The HCV genome is a positive-sense RNA molecule of approximately 9500 nucleotides. There are highly conserved 5' and 3' untranslated regions flanking an approximately 9000 nucleotide single open reading frame which encodes a large polyprotein of about 3000 amino acids [2]. This protein undergoes posttranslational processing by host and viral enzymes to form the structural and nonstructural proteins and enzymes of the virus.
The 5' terminus of the viral RNA is an untranslated region (5' UTR) known to be essential for replication; it contains elements felt to coordinate viral protein synthesis. It is not surprising that this region is highly conserved, and therefore serves as a useful target for amplification in diagnostic assays.
VIRAL HETEROGENEITY — The polymerase enzyme of RNA viruses such as HCV lacks proofreading ability and is therefore unable to correct copying errors made during viral replication. Many of these nucleotide changes result in a nonfunctional genome or a replication incompetent virus (lethal mutants). However, others persist and account for the tremendous viral diversity that is characteristic of HCV. This heterogeneity is extremely important in the diagnosis of infection, pathogenesis of disease, and the response to treatment; it prevents the development of conventional vaccines, allows the virus to escape eradication by the host's immune system, and affects the completeness of the response to antiviral therapies such as interferon [3].
Viral heterogeneity takes several forms depending upon the degree of diversity:
●Quasispecies are families of different, but highly similar, strains that develop within an infected host over time. Nucleotide sequence homology is greater than 95 percent.
●Over decades and centuries, the degree of HCV diversity has evolved into several distinct genotypes of the virus [4]. Sequence homology between genotypes is less than 80 percent. There are six genotypes and numerous subtypes of HCV.
Quasispecies — Differences between quasispecies families are usually only apparent in the most rapidly changing parts of the genome (hypervariable regions). Typically, a single dominant sequence changes with time, being replaced by one or more minor populations due to external pressures (eg, the host immune system) on the quasispecies. One group of investigators generated more than one hundred clones of the most genetically heterogeneous region of a single HCV isolate; they found 19 unique sequences, confined largely to the first hypervariable region (HVR1) of the E2 envelope protein [5].
The clinical implications of quasispecies are not yet entirely understood, although there is some evidence that the quasispecies may be important in the persistence of virus, natural history of infection, and the response to treatment. In one study of 59 patients with chronic HCV infection, increased quasispecies heterogeneity (eg, more than two predominant families of quasispecies) correlated with a longer estimated duration of HCV infection, presumed route of infection (transfusion), increased serum HCV-RNA level, and genotype 1 [6] (see 'Genotypes' below). Patients who had a sustained response to interferon had less pretreatment quasispecies heterogeneity than those who either relapsed or had no response to treatment.
Another report, in which HCV quasispecies were determined in liver samples, found that different quasispecies were compartmentalized within specific regions in the liver, and that the degree of compartmentalization was greater in histologically advanced disease [7]. Another study found that HIV-positive patients had a more diversified HCV population compared with HIV-negative patients, possibly due to less selective pressure from the immune system [8].
This genetic diversity of HCV may allow it to escape host immune surveillance, thereby resulting in virus persistence and a lack of protective immunity [3,5,9]. In one study, for example, markers of viral replication and host immunity were studied in five chimpanzees sequentially inoculated over a period of three years with different HCV strains [3]. Each rechallenge of a convalescent chimpanzee with the same or a different HCV strain resulted in reinfection. Reinfection has also been observed in multiple transfused patients [10]. The genetic diversity of HCV has obvious implications for vaccine development.
Genotypes — Six major genotypes of HCV have been defined, with more than 50 subtypes described; the most common subtypes are 1a, 1b, 2a, and 2b [11,12]. Sporadic viral isolates distinct from all others have been categorized as a seventh and eighth genotype [13,14].
The evolution of genotypes has probably been influenced by several factors, including immune selection, infection patterns, replication efficiency, and population migration. Thus, there is a distinct geographic distribution of HCV genotypes (figure 1) [15-17]:
●Genotype 1 is most common (60 to 75 percent of isolates) in the United States, Latin America, and Europe; genotypes 2 and 3 are less common in these areas, while genotypes 4, 5, and 6 are rare.
●Genotype 3 is most common in India, the Far East, and Australia.
●Genotype 4 is most common in Africa and the Middle East and appears to be emerging more frequently in Europe among injection drug users and men having sex with men, possibly related to immigration to Europe from North Africa.
●Genotype 5 is most common in South Africa.
●Genotype 6 is most common in Hong Kong and Vietnam.
Determination of HCV genotype is essential to making decisions about treatment, as the regimens, dosing, and duration of therapy vary across the genotypes. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Regimen selection' and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)
SUMMARY
●The genetic organization and protein products of the hepatitis C virus (HCV) classify it in the Flaviviridae family, although its diversity is great enough for it to be classified as a separate genus. (See 'Introduction' above.)
●The HCV genome is a positive-sense RNA molecule of approximately 9500 nucleotides. There are highly conserved 5' and 3' untranslated regions flanking an approximately 9000 nucleotide single open reading frame which encodes a large polyprotein of about 3000 amino acids. (See 'Viral genome and replication' above.)
●The polymerase enzyme of RNA viruses such as HCV lacks proofreading ability and is therefore unable to correct copying errors made during viral replication. This leads to heterogeneity that is extremely important in the diagnosis of infection, pathogenesis of disease, and the response to treatment. (See 'Viral genome and replication' above.)
●Viral heterogeneity takes several forms depending upon the degree of diversity:
•Quasispecies are families of different but highly similar strains that develop within an infected host over time. Nucleotide sequence homology is greater than 95 percent. (See 'Quasispecies' above.)
•Over decades and centuries, the degree of HCV diversity has evolved into several distinct genotypes of the virus. Sequence homology between genotypes is less than 80 percent. There are six major genotypes and numerous subtypes of HCV. (See 'Genotypes' above.)
