Hepatitis C virus
Electron micrograph of hepatitis C virus purified from cell culture. Scale: black bar = 50 nanometres
Virus classification
Group:
Group IV ((+)ssRNA)
Family:
Genus:
Type species
Hepatitis C virus

Hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. Hepatitis C virus is the cause of hepatitis C in humans.

Structure

Simplified diagram of the structure of the Hepatitis C virus particle

The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further encased in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoproteins, E1 and E2, are embedded in the lipid envelope.[1]

Genome

Genome organisation of Hepatitis C virus

Hepatitis C virus has a positive sense single-stranded RNA genome. The genome consists of a single open reading frame that is 9600 nucleotide bases long.[2] This single open reading frame is translated to produce a single protein product, which is then further processed to produce smaller active proteins.

At the 5' and 3' ends of the RNA are the UTR, that are not translated into proteins but are important to translation and replication of the viral RNA. The 5' UTR has a ribosome binding site[3] (IRES — Internal ribosome entry site) that starts the translation of a very long protein containing about 3,000 amino acids. The core domain of the hepatitis C virus (HCV) IRES contains a four-way helical junction that is integrated within a predicted pseudoknot.[4] The conformation of this core domain constrains the open reading frame's orientation for positioning on the 40S ribosomal subunit. The large pre-protein is later cut by cellular and viral proteases into the 10 smaller proteins that allow viral replication within the host cell, or assemble into the mature viral particles.[5]

Structural proteins made by the hepatitis C virus include Core protein, E1 and E2; nonstructural proteins include NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A, and NS5B.

Replication

Replication of HCV involves several steps. The virus replicates mainly in the hepatocytes of the liver, where it is estimated that daily each infected cell produces approximately fifty virions (virus particles) with a calculated total of one trillion virions generated. The virus may also replicate in peripheral blood mononuclear cells, potentially accounting for the high levels of immunological disorders found in chronically-infected HCV patients. HCV has a wide variety of genotypes and mutates rapidly due to a high error rate on the part of the virus' RNA-dependent RNA polymerase. The mutation rate produces so many variants of the virus it is considered a quasispecies rather than a conventional virus species.[6] Entry into host cells occur through complex interactions between virions and cell-surface molecules CD81, LDL receptor, SR-BI, DC-SIGN, Claudin-1, and Occludin.[7][8]

A simplified diagram of the HCV replication cycle

Once inside the hepatocyte, HCV takes over portions of the intracellular machinery to replicate.[9] The HCV genome is translated to produce a single protein of around 3011 amino acids. The polyprotein is then proteolytically processed by viral and cellular proteases to produce three structural (virion-associated) and seven nonstructural (NS) proteins. Alternatively, a frameshift may occur in the Core region to produce an Alternate Reading Frame Protein (ARFP).[10] HCV encodes two proteases, the NS2 cysteine autoprotease and the NS3-4A serine protease. The NS proteins then recruit the viral genome into an RNA replication complex, which is associated with rearranged cytoplasmic membranes. RNA replication takes places via the viral RNA-dependent RNA polymerase NS5B, which produces a negative-strand RNA intermediate. The negative strand RNA then serves as a template for the production of new positive-strand viral genomes. Nascent genomes can then be translated, further replicated, or packaged within new virus particles. New virus particles are thought to bud into the secretory pathway and are released at the cell surface.

Genotypes

Based on genetic differences between HCV isolates, the hepatitis C virus species is classified into six genotypes (1-6) with several subtypes within each genotype (represented by letters). Subtypes are further broken down into quasispecies based on their genetic diversity. The preponderance and distribution of HCV genotypes varies globally. For example, in North America, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In Europe, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa. Genotype is clinically important in determining potential response to interferon-based therapy and the required duration of such therapy. Genotypes 1 and 4 are less responsive to interferon-based treatment than are the other genotypes (2, 3, 5 and 6).[11] Duration of standard interferon-based therapy for genotypes 1 and 4 is 48 weeks, whereas treatment for genotypes 2 and 3 is completed in 24 weeks.

Infection with one genotype does not confer immunity against others, and concurrent infection with two strains is possible. In most of these cases, one of the strains removes the other from the host in a short time. This finding opens the door to replace strains non-responsive to medication with others easier to treat.[12]

Genotype 6 is most common in Asia and represents perhaps 1/3 of all cases.[13] It is a diverse genotype and now contains genotypes that were originally classified as genotypes 7, 8, 9 and 11.[14]

Evolution

The major genotypes diverged about 300–400 years ago from the ancestor virus. [15] The minor genotypes diverged about 200 years ago from their major genotypes. All of the extant genotypes appear to have evolved from genotype 1 subtype 1b.

An examination of the genotype 6 strains suggests an earlier date of evolution: ∼1,100 to 1,350 years before the present (95% credible region, 600 to >2,500 years ago).[16] The estimated rate of mutation was 1.8 × 10−4; 95% credible region 0.9 × 10−4 to 2.9 × 10−4.

An estimate of the mutation rate based on genomes from the United States and Japan gave a rate of 1.78 × 10−4 substitutions/site/year (95% credible region, 1.11 × 10−4 to 2.6 × 10−4). A very similar estimate was obtained under the relaxed clock models, 1.72 × 10−4 substitutions/site/year (95% credible region, 0.91 × 10−4 to 2.7×10−4)[17] Genotype 1 first appeared in Japan around 1882 and in the US in 1910. The major increase in the effective population size in Japan occurred in the 1930s and in the US in the 1960s. Japan introduced intrevenous antimony in 1921 for the treatment of Schistosoma japonicum. Genotype 1a infections in the United States, Brazil, and Indonesia began to increase exponentially during the 1940s and 1950s.[18]

A study in Turkey suggested that the genotype 1b found there presently originated in Greece ~1900 and spread to Turkey between 1920 and 1930.[19] The estimated mutation rate mean evolutionary rate was 0.84 × 10-3 substitutions/site/year (95% credible interval 0.16-1.5 × 10-3). The effective number of strains in circulation reached a plateau after the year 2000. This may reflect improvements in blood transfusion.

A study in France of genotype 5a found the most probable date of origin of this genotype in France was 1939 [95% credible interval: 1921-1956]).[20] These dates agree with those derived from other data.

The genotype 1b appears to have been introduced to Bogota, Columbia in 1950.[21] Its effective population size increased at an exponential rate between 1970 to 1990. Its increase ceased presumably as a result of the introduction of improved blood transfusion practices.

An analysis of the genotype 1b in Argentina estimated the mutation rate to be between 3.24 x 10-3 and 7.41 x 10-3 substitutions/site/year (s/s/y).[22] This genotype appears to have been introduced in the 1950s.

Genotype 2 in West Africa appears to have evolved ~1540 (95% highest posterior density interval: 1380-1680).[23] It spread subsequently to Cameroon in 1630 (95% highest posterior density interval: 1470-1760) Between 1630 to 1900 the virus spread slowly within the West African population but underwent an exponential increase in effective population size between from 1920 to 1960 in Cameroon.

In Cameroon genotypes 1 and 4 appeared ~1500 (95% confidence intervals 1300-1650 and 1350-1700 respectively).[24] Both genotypes underwent an exponential increase in effective population size between from 1920 to 1960. During this period a mass campaign against trypanosomiasis and mass vaccinations in Cameroon were undertaken which probably accounts for this observed growth in population size.

In Egypt the effective population size increased exponentially between 1930 and 1955.[25] It is likely that this spread was caused by the extensive antischistosomiasis injection campaigns that used intravenous antimony at that time.

In China genotype 1b occurs in two main clades which seem to have originated in the 1960s.[26] The effective population size increased significantly from the 1970s to 1990 when its growth stalled presumably due to the introduction of improved blood products.

Vaccination

Unlike hepatitis A and B, there is currently no vaccine to prevent hepatitis C infection.[27]

In a 2006 study, 60 patients received four different doses of an experimental hepatitis C vaccine. All the patients produced antibodies that the researchers believe could protect them from the virus.[28] Nevertheless, as of 2008 vaccines are still being tested.[29][30]

Current research

Structure of the IRES located in the 5'-UTR of HCV

Current research is focused on small-molecule inhibitors of the viral protease, RNA polymerase and other nonstructural genes. Boceprevir by Merck was approved on May 13, 2011.[31] Telaprevir by Vertex Pharmaceuticals Inc was also approved on May 23, 2011.

The study of HCV has been hampered by the narrow host range of HCV.[32] The use of replicons has been successful but these have only been recently discovered.[33] HCV, as with most all RNA viruses, exists as a viral quasispecies, making it very difficult to isolate a single strain or receptor type for study.[34]

Stability in the environment

Like many viruses, the hepatitis C virus is gradually inactivated outside the body of a host. The presence of heat can have a drastic impact on the virus's lifespan outside the body. The virus can remain infectious outside a host for about sixteen days at 25°C and two days at 37°C, while it can remain active for more than six weeks at temperatures less than or equal to 4°C. When heated to temperatures of 60°C and 65°C, however, the hepatitis C virus can be inactivated in eight and four minutes, respectively.[35]

See also

References

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