Hepatitis C virus
|Hepatitis C virus|
|Electron micrograph of hepatitis C virus purified from cell culture. Scale: black bar = 50 nanometres|
|Group:||Group IV ((+)ssRNA)|
|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 and some cancers such as liver cancer (Hepatocellular carcinoma, abbreviated HCC) and lymphomas in humans.
The hepatitis C virus belongs to the genus Hepacivirus, a member of the family Flaviviridae. Until recently it was considered to be the only member of this genus. However a member of this genus has been discovered in dogs—canine hepacivirus. There is also at least one virus in this genus that infects horses. Several additional viruses in the genus have been described in bats and rodents.
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.
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. 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 (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. 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. Structural proteins made by the hepatitis C virus include Core protein, E1 and E2; nonstructural proteins include NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
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The proteins of this virus are arranged along the genome in the following order: N terminal-core-envelope (E1)–E2–p7-nonstructural protein 2 (NS2)–NS3–NS4A–NS4B–NS5A–NS5B–C terminal. The mature nonstructural proteins (NS2 to NS5B) generation relies on the activity of viral proteinases. The NS2/NS3 junction is cleaved by a metal dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining cleavages downstream from this site are catalysed by a serine proteinase also contained within the N-terminal region of NS3.
The core protein has 191 amino acids and can be divided into three domains on the basis of hydrophobicity: domain 1 (residues 1–117) contains mainly basic residues with two short hydrophobic regions; domain 2 (residues 118–174) is less basic and more hydrophobic and its C-terminus is at the end of p21; domain 3 (residues 175–191) is highly hydrophobic and acts as a signal sequence for E1 envelope protein.
Both envelope proteins (E1 and E2) are highly glycosylated and important in cell entry. E1 serves as the fusogenic subunit and E2 acts as the receptor binding protein. E1 has 4–5 N-linked glycans and E2 has 11 N-glycosylation sites.
The p7 protein is dispensable for viral genome replication but plays a critical role in virus morphogenesis. This protein is a 63 amino acid membrane spanning protein which locates itself in the endoplasmic reticulum. Cleavage of p7 is mediated by the endoplasmic reticulum's signal peptidases. Two transmembrane domains of p7 are connected by a cytoplasmic loop and are oriented towards the endoplasmic reticulum's lumen.
NS2 protein is a 21–23 kiloDalton (kDa) transmembrane protein with protease activity.
NS3 is 67 kDa protein whose N-terminal has serine protease activity and whose C-terminal has NTPase/helicase activity. It is located within the endoplasmic reticulum and forms a heterodimeric complex with NS4A—a 54 amino acid membrane protein that acts as a cofactor of the proteinase.
NS4B is a small (27 kDa) hydrophobic integral membrane protein with 4 transmembrane domains. It is located within the endoplasmic reticulum and plays an important role for recruitment of other viral proteins. It induces morphological changes to the endoplasmic reticulum forming a structure termed the membranous web.
NS5A is a hydrophilic phosphoprotein which plays an important role in viral replication, modulation of cell signaling pathways and the interferon response. It is known to bind to endoplasmic reticulum anchored human VAP proteins.
The NS5B protein (65 kDa) is the viral RNA dependent RNA polymerase. NS5B has the key function of replicating the HCV’s viral RNA by using the viral positive RNA strand as its template and catalyzes the polymerization of ribonucleoside triphosphates (rNTP) during RNA replication. Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK (HCV-BK, genotype 1). The structure can be represented by a right hand shape with fingers, palm, and thumb. The encircled active site, unique to NS5B, is contained within the palm structure of the protein. Recent studies on NS5B protein genotype 1b strain J4’s (HC-J4) structure indicate a presence of an active site where possible control of nucleotide binding occurs and initiation of de-novo RNA synthesis. De-novo adds necessary primers for initiation of RNA replication. Current research attempts to bind structures to this active site to alter its functionality in order to prevent further viral RNA 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. 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.
Once inside the hepatocyte, HCV takes over portions of the intracellular machinery to replicate. 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). 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.
The virus replicates on intracellular lipid membranes. The endoplasmic reticulum in particular are deformed into uniquely shaped membrane structures termed 'membranous webs'. These structures can be induced by sole expression of the viral protein NS4B. The core protein associates with lipid droplets and utilises microtubules and dyneins to alter their location to a perinuclear distribution. Release from the hepatocyte may involve the very low density lipoprotein secretory pathway.
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 lower-cased letters). Subtypes are further broken down into quasispecies based on their genetic diversity. Genotypes differ by 30–35% of the nucleotide sites over the complete genome. The difference in genomic composition of subtypes of a genotype is usually 20–25%. Subtypes 1a and 1b are found worldwide and cause 60% of all cases.
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). The 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. Sustained virological responses occur in 70% of genotype 1 cases, ~90% of genotypes 2 and 3, ~65% of genotype 4 and ~80% of genotype 6. In addition people of African descent are much less likely to clear the infection when infected with genotypes 1 or 4  and substantial proportion of this lack of response to treatment has been traced down to a single nucleotide polymorphism (SNP) on chromosome 19 that is predictive of treatment success. HCV genotypes 1 and 4 have been distributed endemically in overlapping areas of West and Central Africa, infecting for centuries human populations carrying the genetic polymorphism in question. This has prompted scientists to suggest that the protracted persistence of HCV genotypes 1 and 4 in people of African origin is an evolutionary adaptation over many centuries to these populations’ immunogenetic responses.
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 replacing strains non-responsive to medication with others easier to treat.
Hepatitis C virus is predominantly a blood-borne virus, with very low risk of sexual or vertical transmission. Because of this mode of spread the key groups at risk are injecting drug users (IDUs), people who are transfused blood, recipients of blood products and sometimes patients on haemodialysis. Common setting for transmission of HCV is also intra-hospital (nosocomial) transmission, when practices of hygiene and sterilization are not correctly followed in the clinic. A number of cultural or ritual practices have been proposed as a potential historical mode of spread for hepatitis C virus, including circumcision, genital mutilation, ritual scarification, traditional tattooing and acupuncture. It has also been argued that given the extremely prolonged periods of persistence of HCV in humans, even very low and undetectable rates of mechanical transmission via biting insects may be sufficient to maintain endemic infection in the tropic, where people receive large number of insect bites.
Identifying of the origin of this virus has been difficult but genotypes 1 and 4 appear to share a common origin. A Bayesian analysis suggests that the major genotypes diverged about 300–400 years ago from the ancestor virus. 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.
A study of 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). The estimated rate of mutation was 1.8 × 10−4 (95% credible region 0.9 × 10−4 to 2.9 × 10−4). This genotype may be the ancestor of the other genotypes.
A study of European, USA and Japanese isolates suggested that the date of origin of genotype 1b was ~1925. The estimated dates of origin of types 2a and 3a were 1917 and 1943 respectively. The time of divergence of types 1a and 1b was estimated to be 200–300 years.
A study of genotype 1a and 1b estimated the dates of origin to be 1914–1930 (95% credible interval: 1802–1957) for type 1a and 1911–1944 (95% credible interval: 1806–1965) for type 1b. Both types 1a and 1b underwent massive expansions in their effective population size between 1940 and 1960. The expansion of HCV subtype 1b preceded that of subtype 1a by at least 16 years (95% credible interval: 15–17 years). Both types appear to have spread from the developed world to the developing world.
The genotype 2 strains from Africa can be divided into four clades that correlate with their country of origin: (1) Cameroon and Central African Republic (2) Benin, Ghana and Burkina Faso (3) Gambia, Guinea, Guinea-Bissau and Senegal (4) Madagascar. There is also strong evidence now for the dissemination of hepatitis C virus genotype 2 from West Africa to the Caribbean by the Trans-Atlantic slave trade 
Genotype 3 is thought to have its origin in South East Asia.
These dates from these various countries suggests that this virus may have evolved in South East Asia and was spread to West Africa by traders from Western Europe. It was later introduced into Japan once that country's self-imposed isolation was lifted. Once introduced to a country its spread has been influenced by many local factors including blood transfusions, vaccination programmes, intravenous drug use and treatment regimes. Given the reduction in the rate of spread once screening for Hepatitis C in blood products was implemented in the 1990s it would seem that at least in recent times blood transfusion has been an important method of spreading for this virus. Additional work is required to determine the dates of evolution of the various genotypes and the timing of their spread across the globe.
The study of HCV has been hampered by the narrow host range of HCV. The use of replicons has been successful but these have only been recently discovered. HCV, as with most RNA viruses, exists as a viral quasispecies, making it very difficult to isolate a single strain or receptor type for study.
Current research is focused on small-molecule inhibitors of the viral protease, RNA polymerase and other nonstructural genes. Two agents — Boceprevir by Merck and Telaprevir by Vertex Pharmaceuticals Inc—both inhibitors of NS3 protease were approved for use on May 13, 2011 and May 23, 2011 respectively.
A possible association between low Vitamin D levels and a poor response to treatment has been reported. In vitro work has shown that Vitamin D may be able to reduce viral replication. While this work looks promising the results of clinical trials are awaited. However, it has been proposed that Vitamin D supplementation is important in addition to standard treatment, in order to enhance treatment response.
Naringenin has been shown to block the assembly of intracellular infectious viral particles without affecting intracellular levels of the viral RNA or protein. Although the research is relatively new, naringenin may offer new insight into HCV therapeutic target.
Other agents that are under investigation include nucleoside/nucleotide analogue inhibitors and non nucleoside inhibitors of the RNA dependent RNA polymerase, inhibitors of nonstructural protein 5A and host targeted compounds such as cyclophilin inhibitors and silibinin.
Sofosbuvir for use against chronic hepatitis C infection was approved by the FDA December 6, 2013. It has been reported to be the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon. On November 22, the FDA approved simeprevir for use in combination with peginterferon-alfa and ribavirin. Simeprevir has been approved in Japan for the treatment of chronic hepatitis C infection, genotype 1.
There is also current experimental research on non drug related therapies. Oxymatrine, for example, is a root extract found in the continent of Asia that has been reported to have antiviral activity against HCV in cell cultures and animal studies. Small and promising human trials have shown no serious side effects and beneficial results, but they were too small to generalize conclusions.
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