Hepatitis C virus
Encyclopedia
Hepatitis C virus 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.
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 glycoprotein
s, 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 protease
s 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, NS4
, NS4A, NS4B, NS5
, NS5A, and NS5B.
s 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 disorder
s found in chronically-infected HCV patients. HCV has a wide variety of genotype
s 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.
, 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).
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.
to prevent hepatitis C infection.
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. Nevertheless, as of 2008 vaccines are still being tested.
, RNA polymerase
and other nonstructural genes. Boceprevir
by Merck was approved on May 13, 2011. 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. The use of replicons
has been successful but these have only been recently discovered. 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.
Nanometre
A nanometre is a unit of length in the metric system, equal to one billionth of a metre. The name combines the SI prefix nano- with the parent unit name metre .The nanometre is often used to express dimensions on the atomic scale: the diameter...
in size), enveloped
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
, positive-sense single-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
of the family Flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...
. Hepatitis C virus is the cause of hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
in humans.
Structure
Truncated icosahedron
In geometry, the truncated icosahedron is an Archimedean solid, one of thirteen convex isogonal nonprismatic solids whose faces are two or more types of regular polygons.It has 12 regular pentagonal faces, 20 regular hexagonal faces, 60 vertices and 90 edges....
protective shell of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, and further encased in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s, E1 and E2, are embedded in the lipid envelope.
Genome
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. The genome consists of a single open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
that is 9600 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
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
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
binding site (IRES - Internal ribosome entry site
Internal ribosome entry site
An internal ribosome entry site, abbreviated IRES, is a nucleotide sequence that allows for translation initiation in the middle of a messenger RNA sequence as part of the greater process of protein synthesis...
) 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 protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s 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
E1 (HCV)
E1 is a viral structural protein found in hepatitis C....
and E2
E2 (HCV)
E2 is a viral structural protein found in hepatitis C amongst other viruses, including HPV....
; nonstructural proteins include NS2
NS2 (HCV)
NS2 is a viral protein found in hepatitis C....
, NS3, NS4
NS4 (HCV)
NS4 is a viral protein found in hepatitis C....
, NS4A, NS4B, NS5
NS5 (HCV)
NS5 is a viral protein found in hepatitis C....
, NS5A, and NS5B.
Replication
Replication of HCV involves several steps. The virus replicates mainly in the hepatocyteHepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s 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 disorder
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
s found in chronically-infected HCV patients. HCV has a wide variety of genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
s and mutates rapidly due to a high error rate on the part of the virus' RNA-dependent RNA polymerase
RNA-dependent RNA polymerase
RNA-dependent RNA polymerase , , or RNA replicase, is an enzyme that catalyzes the replication of RNA from an RNA template...
. The mutation rate produces so many variants of the virus it is considered a quasispecies
Quasispecies model
The quasispecies model is a description of the process of the Darwinian evolution of certain self-replicating entities within the framework of physical chemistry...
rather than a conventional virus species. Entry into host cells occur through complex interactions between virions and cell-surface molecules CD81
CD81
CD81 molecule, also known as CD81 , is a protein which in humans is encoded by the CD81 gene...
, LDL receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
, SR-BI
SCARB1
Scavenger receptor class B member 1 also known as SR-BI is a protein that in humans is encoded by the SCARB1 gene. SR-BI functions as a receptor for high-density lipoprotein....
, DC-SIGN
DC-SIGN
DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene....
, Claudin-1
CLDN1
Claudin-1 is a protein that in humans is encoded by the CLDN1 gene. It belongs to the group of claudins.-Interactions:CLDN1 has been shown to interact with CLDN5 and CLDN3.-Further reading:...
, and Occludin
Occludin
Occludin is a protein that in humans is encoded by the OCLN gene.Occludin is a 65-kDa integral plasma-membrane protein located at the tight junctions, described for the first time in 1993 by Shoichiro Tsukita...
.
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
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 AmericaNorth America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
. Genotype is clinically important in determining potential response to interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
-based therapy and the required duration of such therapy. Genotypes 1 and 4 are less responsive to interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
-based treatment than are the other genotypes (2, 3, 5 and 6).
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.
Vaccination
Unlike hepatitis A and B, there is currently no vaccineVaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
to prevent hepatitis C infection.
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. Nevertheless, as of 2008 vaccines are still being tested.
Current research
Current research is focused on small-molecule inhibitors of the viral proteaseProtease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
, RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
and other nonstructural genes. Boceprevir
Boceprevir
Boceprevir is a protease inhibitor used as a treatment for hepatitis C genotype 1. It binds to HCV nonstructural 3 active site....
by Merck was approved on May 13, 2011. 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. The use of replicons
Replicon (genetics)
A replicon is a DNA molecule or RNA molecule, or a region of DNA or RNA, that replicates from a single origin of replication.For most prokaryotic chromosomes, the replicon is the entire chromosome. One notable exception found comes from archaea, where two Sulfolobus species have been shown to...
has been successful but these have only been recently discovered. HCV, as with most all RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
viruses, exists as a viral quasispecies
Viral quasispecies
A viral quasispecies is a group of viruses related by a similar mutation or mutations, competing within a highly mutagenic environment. The theory predicts that a viral quasispecies at a low but evolutionarily neutral and highly connected region in the fitness landscape will outcompete a...
, making it very difficult to isolate a single strain or receptor type for study.
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.See also
- Hepatitis C virus stem-loop VIIHepatitis C virus stem-loop VIIHepatitis C virus stem-loop VII is a regulatory element found in the coding region of the RNA-dependent RNA polymerase gene, NS5B. Similarly to stem-loop IV, the stem-loop structure is important for colony formation, though its exact function and mechanism are unknown.-See also:*Hepatitis C...
- Hepatitis C virus 3'X elementHepatitis C virus 3'X elementThe Hepatitis C virus 3'X element is an RNA element which contains three stem-loop structures that are essential for replication.-See also:*Hepatitis C alternative reading frame stem-loop*Hepatitis C virus cis-acting replication element...
- Hepatitis C virus (HCV) cis-acting replication element (CRE)Hepatitis C virus (HCV) cis-acting replication element (CRE)The Hepatitis C virus cis-acting replication element is an RNA element which is found in the coding region of the RNA-dependent RNA polymerase NS5B...