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51-452: Nonstructural protein 4B ( NS4B ) is a viral protein found in the hepatitis C virus . It has mass of 27 kDa and probably involved in process of intracellular membrane structure formation to allow virus replication . This virus -related article is a stub . You can help Misplaced Pages by expanding it . Viral protein Most viral structural proteins are components for the capsid and

102-452: A lipid membrane envelope that is 55 to 65 nm in diameter. Two viral envelope glycoproteins , E1 and E2 , are embedded in the lipid envelope. They take part in viral attachment and entry into the cell. Within the envelope is an icosahedral core that is 33 to 40 nm in diameter. Inside the core is the RNA material of the virus. E1 and E2 are covalently bonded when embedded in

153-427: A complex, priming them for later HCV infection processes. As the immune system is triggered, macrophages increase the amount of TNF-α around the hepatocytes which are being infected. This triggers the migration of occludin, which is another tight-junction complex, to the basolateral membrane. The HCV particle is ready to enter the cell. These interactions lead to the endocytosis of the viral particle. This process

204-559: 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 place via the viral RNA-dependent RNA polymerase NS5B, which produces

255-473: 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. The virus replicates on intracellular lipid membranes. The endoplasmic reticulum in particular is deformed into uniquely shaped membrane structures termed 'membranous webs'. These structures can be induced by sole expression of

306-492: A number of different viral proteins make up the capsid, and each of these viral proteins are coded for by one gene from the viral genome . The structure of the capsid allows the virus to use a small number of viral genes to make a large capsid. Several protomers , oligomeric (viral) protein subunits, combine to form capsomeres , and capsomeres come together to form the capsid. Capsomeres can arrange into an icosahedral , helical, or complex capsid, but in many viruses, such as

357-464: 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 pending. However, it has been proposed that vitamin D supplementation is important in addition to standard treatment, in order to enhance treatment response. Naringenin , a flavonoid found in grapefruit and other fruits and herbs, has been shown to block

408-433: A process called budding. The viral envelope is made up of a lipid bilayer embedded with viral proteins, including viral glycoproteins . These viral glycoproteins bind to specific receptors and coreceptors on the membrane of host cells, and they allow viruses to attach onto their target host cells. Some of these glycoproteins include: Viral glycoproteins play a critical role in virus-to-cell fusion. Virus-to-cell fusion

459-478: A single open reading frame that is 9,600 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. This is why on publicly available databases, such as the European Bioinformatics Institute , the viral proteome only consists of 2 proteins. At the 5′ and 3′ ends of the RNA are

510-500: A wide range of structural conformations to be discovered. Viral membrane fusion proteins have been grouped into four different classes, and each class is identified by characteristic structural conformations: Viral nonstructural proteins are proteins coded for by the genome of the virus and are expressed in infected cells. However, these proteins are not assembled in the virion. During the replication of viruses, some viral nonstructural proteins carry out important functions that affect

561-488: Is aided by clathrin proteins. Once inside an early endosome, the endosome and the viral envelope fuse and the RNA is allowed into the cytoplasm. HCV takes over portions of the intracellular machinery to replicate. The HCV genome is translated to produce a single protein of around 3,011 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,

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612-412: 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 beneficial results and no serious side effects, but they were too small to generalize conclusions. On October 5, 2020, it

663-590: 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 HCV, 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

714-461: Is an evolutionary adaptation of HCV 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 outcompetes the other in a short time. This finding may be useful in treatment, in replacing strains non-responsive to medication with others easier to treat. When two viruses infect

765-591: 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 protease also contained within the N-terminal region of NS3. An 11th protein has also been described. This protein is encoded by a +1 frameshift in the capsid gene. It appears to be antigenic but its function is unknown. Replication of HCV involves several steps. The virus replicates mainly in

816-433: Is initiated when viral glycoproteins bind to cellular receptors. The fusion of the viral envelope with the cellular membrane requires high energy to occur. Viral membrane fusion proteins act as catalysts to overcome this high energy barrier . Following viral glycoprotein binding to cellular receptors , viral membrane fusion proteins undergo a change in structure conformation. This change in conformation then facilitates

867-409: 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 cleaved 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

918-625: Is normally utilized to bud vesicles out of the cell. The only limitation to this hypothesis is that the pathway is normally used for cellular budding , and it is not known how HCV would commandeer the ESCRT pathway for use with the endoplasmic reticulum. 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 lowercase letters). Subtypes are further broken down into quasispecies based on their genetic diversity. Genotypes differ by 30–35% of

969-466: Is proposed to be caused by a single-nucleotide polymorphism (SNP) on chromosome 19 of the human genome 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

1020-553: 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

1071-400: 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. In the liver,

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1122-512: The mammalian genome to allow membrane fusion in placental morphogenesis. Hepatitis C virus Hepatitis C virus HCV human hepatitis C virus The hepatitis C virus ( HCV ) is a small (55–65 nm in size), enveloped , positive-sense single-stranded RNA virus of the family Flaviviridae . The 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

1173-450: The untranslated regions (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 or internal ribosome entry site (IRES) that initiates the translation of a very long protein containing about 3,000 amino acids. The core domain of the HCV IRES contains a four-way helical Holliday junction that

1224-484: The HCV particles are brought into the hepatic sinusoids by blood flow. These sinusoids neighbor hepatocyte cells. HCV is able to pass through the endothelium of the sinusoids and make its way to the basolateral surface of the hepatocyte cells. 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

1275-513: The assembly of intracellular infectious viral particles without affecting intracellular levels of the viral RNA or protein. Other agents that are under investigation include nucleoside and nucleotide analogue inhibitors and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, inhibitors of NSP5A, and host-targeted compounds such as cyclophilin inhibitors and silibinin . Sofosbuvir for use against chronic hepatitis C infection

1326-457: The complex, and NS4B interacts with them and binds to viral RNA . The immune response of a host to an infected cell can be adjusted through the immunomodulatory properties of viral nonstructural proteins. Many species of large DNA viruses encode proteins which subvert host immune response, allowing proliferation of the virus. Such proteins hold potential in developing new bio-pharmaceutical treatments for inflammatory disease in humans, as

1377-490: The destabilization and fusion of the viral envelope with the cellular membrane by allowing fusion loops (FLs) or hydrophobic fusion peptides (FPs) on the viral envelope to interact with the cell membrane. Most viral membrane fusion proteins would end up in a hairpin-like conformation after fusion, in which FLs/FPs and the transmembrane domain are all on the same side of the protein. Viral glycoproteins and their three-dimensional structures, before and after fusion, have allowed

1428-481: 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 for the dissemination of HCV genotype 2 from West Africa to the Caribbean by the trans-Atlantic slave trade . Genotype 3

1479-514: The envelope of HCV and are stabilized by disulfide bonds . E2 is globular and seems to protrude 6 nm out from the envelope membrane according to electron microscope images. These glycoproteins play an important role in the interactions hepatitis C has with the immune system. A hypervariable region , the hypervariable region 1 (HVR1) can be found on the E2 glycoprotein. HVR1 is flexible and quite accessible to surrounding molecules. HVR1 helps E2 shield

1530-422: The envelope of the virus. The genetic material of a virus is stored within a viral protein structure called the capsid. The capsid is a "shield" that protects the viral nucleic acids from getting degraded by host enzymes or other types of pesticides or pestilences. It also functions to attach the virion to its host, and enable the virion to penetrate the host cell membrane. Many copies of a single viral protein or

1581-402: The genome of retroviruses. Most viral accessory proteins only carry out their functions in specific types of cells. Also, they do not have much influence on the replication of the virus. However, in some instances, maintaining the replication of viruses would require the help (and function) of viral accessory proteins. Syncytin is an endogenous retrovirus protein that has been captured in

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1632-417: The genus Hepacivirus , a member of the family Flaviviridae . Before 2011, 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

1683-447: The hepatitis C virus include Core protein, E1 and E2; nonstructural proteins include NS2 , NS3 , NS4A , NS4B , NS5A , and NS5B . 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

1734-423: The herpes simplex virus, an icosahedral capsid is assembled. Three asymmetric and nonidentical viral protein units make up each of the twenty identical triangular faces in the icosahedral capsid. The capsid of some viruses are enclosed in a membrane called the viral envelope. In most cases, the viral envelope is obtained by the capsid from the host cell's plasma membrane when a virus leaves its host cell through

1785-645: 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 —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

1836-417: 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

1887-512: 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 respond to treatment when infected with genotypes 1 or 4. The substantial proportion of this lack of response to treatment

1938-587: The proteins have been proven to subvert inflammatory immune mediators . Viral nonstructural protein NS1 in the West Nile virus prevents complement activation through its binding to a complement control protein, factor H. As a result, complement recognition of infected cells is reduced, and infected cells remain unharmed by the host's immune system. Viral regulatory and accessory proteins have many functions. These viral proteins control and influence viral gene expressions in

1989-463: The reduction in the rate of spread once screening for HCV in blood products was implemented in the 1990s, it would seem that previously blood transfusion was an important method of spread. Additional work is required to determine the dates of evolution of the various genotypes and the timing of their spread across the globe. Unlike hepatitis A and B, there is currently no vaccine to prevent hepatitis C infection. The study of HCV has been hampered by

2040-399: The replication process itself. Similarly, during the assembly of viruses, some of these proteins also carry out important functions that affect the assembly process. Some of these viral nonstructural protein functions are replicon formation, immunomodulation, and transactivation of viral structural protein encoding genes. Viral nonstructural proteins interact with host cell proteins to form

2091-443: The replicon, otherwise known as the replication complex. In the hepatitis C virus , viral nonstructural proteins interact with cellular vesicle membrane transport protein , hVAP-33 , to assemble the replicon. Viral nonstructural 4b ( NS4B ) protein alters the host cell's membrane and starts the formation process of the replication complex. Other viral nonstructural proteins such as NS5A , NS5B , and NS3 , are also recruited to

Hepatitis C virus nonstructural protein 4B - Misplaced Pages Continue

2142-544: The same cell, genetic recombination may occur. Although infrequent, HCV recombination has been observed between different genotypes, between subtypes of the same genotype and even between strains of the same subtype. 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 intravenous drug users (IDUs), recipients of blood products and sometimes patients on haemodialysis . Common setting for transmission of HCV

2193-621: The tropics, where people receive large number of insect bites. Identification 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 common 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: approximately 1,100 to 1,350 years Before Present . The estimated rate of mutation

2244-482: The viral genome, including viral structural gene transcription rates. Viral regulatory and accessory proteins also influence and adjust cellular functions of the host cell, such as the regulation of genes, and apoptosis. In DNA viruses and retroviruses, viral regulatory proteins can enhance viral gene transcription, likewise, these proteins can also enhance host cellular gene transcription too. Viral accessory proteins, also known as auxiliary proteins, are coded for by

2295-528: 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 VLDL secretory pathway. Another hypothesis states that the viral particle may be secreted from the endoplasmic reticulum through the endosomal sorting complex required for transport (ESCRT) pathway. This pathway

2346-431: The virus from the immune system. It prevents CD81 from latching onto its respective receptor on the virus. In addition, E2 can shield E1 from the immune system. Although HVR1 is quite variable in amino acid sequence, this region has similar chemical, physical, and conformational characteristics across many E2 glycoproteins. Hepatitis C virus has a positive sense single-stranded RNA genome . The genome consists of

2397-421: The virus is thought to be able to associate with apolipoproteins . It could surround itself with lipoproteins, partially covering up E1 and E2. Recent research indicates that these apolipoproteins interact with scavenger receptor B1 (SR-B1). SR-B1 is able to remove lipids from the lipoproteins around the virus to better allow for HVR1 contact. Claudin 1, which is a tight-junction protein , and CD81 link to create

2448-445: The virus it is considered a quasispecies rather than a conventional virus species. Entry into host cells occur through complex interactions between virions, especially through their glycoproteins, and cell-surface molecules CD81 , LDL receptor , SR-BI , DC-SIGN , Claudin-1 , and Occludin . The envelope of HCV is similar to very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). Because of this similarity,

2499-438: Was 1.8 × 10 . An experimental study estimated the mutation rate at 2.5–2.9 × 10 base substitutions per site per year. This genotype may be the ancestor of the other genotypes. A study of European, US and Japanese isolates suggested that the date of origin of genotype 1b was approximately in the year 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

2550-544: Was approved by the FDA on 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

2601-404: Was estimated to be 200–300 years. A study of genotype 1a and 1b estimated the dates of origin to be 1914–1930 for type 1a and 1911–1944 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. Both types appear to have spread from the developed world to

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