91-440: The Epstein–Barr virus ( EBV ), formally called Human gammaherpesvirus 4 , is one of the nine known human herpesvirus types in the herpes family , and is one of the most common viruses in humans. EBV is a double-stranded DNA virus . Epstein–Barr virus (EBV) is the first identified oncogenic virus , or a virus that can cause cancer . EBV establishes permanent infection in humans. It causes infectious mononucleosis and
182-552: A memory B cell . Finally, EBV restricts gene expression even further and enters Latency I. Expression of EBNA-1 allows the EBV genome to replicate when the memory B cell divides. Within epithelial cells, only Latency II is possible. In primary infection, EBV replicates in oropharyngeal epithelial cells and establishes Latency III, II, and I infections in B ;lymphocytes. EBV latent infection of B lymphocytes
273-422: A PI3K inhibitor is added to cells, the cytokine synthesis levels are significantly restored. The fact that cytokine levels are not completely restored indicates there is another pathway activated by cmvIL-10 that is inhibiting cytokine system synthesis. The proposed mechanism is that cmvIL-10 activates PI3K which in turn activates PKB (Akt). PKB may then activate mTOR , which may target Stat3 for phosphorylation on
364-583: A consequence, EBV made from B cells are more infectious to epithelial cells, and EBV made from epithelial cells are more infectious to B cells. Viruses lacking the gp42 portion are able to bind to human B cells, but unable to infect. EBV can infect both B cells and epithelial cells. The mechanisms for entering these two cells are different. To enter B cells, viral glycoprotein gp350 binds to cellular receptor CD21 (also known as CR2). Then, viral glycoprotein gp42 interacts with cellular MHC class II molecules. This triggers fusion of
455-588: A decrease in proliferation of PBMCs. This indicates that cmvIL-10 may lack the stimulatory effects that hIL-10 has on these cells. It was found that cmvIL-10 functions through phosphorylation of the Stat3 protein. It was originally thought that this phosphorylation was a result of the JAK-STAT pathway. However, despite evidence that JAK does indeed phosphorylate Stat3, its inhibition has no significant influence on cytokine synthesis inhibition. Another protein, PI3K ,
546-416: A high viscosity , for example, in egg white and blood plasma . Variable surface glycoproteins allow the sleeping sickness Trypanosoma parasite to escape the immune response of the host. The viral spike of the human immunodeficiency virus is heavily glycosylated. Approximately half the mass of the spike is glycosylation and the glycans act to limit antibody recognition as the glycans are assembled by
637-460: A limited lifespan and eventually die, but when EBV infects B lymphocytes, it alters their behavior, making them "immortal" in the sense that they can keep dividing and surviving much longer than usual. This allows the virus to persist in the body for the individual's lifetime. When EBV infects B cells in vitro , lymphoblastoid cell lines eventually emerge that are capable of indefinite growth. The growth transformation of these cell lines
728-524: A person with a novel or reactivated infection since EBNA1 levels in the nucleus and nucleolus are higher during active attack of the body because of the constant replication and take-over of cells in the body. The complexities of Epstein-Barr virus (EBV) persistence and its integration into host genomes have been explored. Research involving tissue samples from individuals with various conditions revealed that viral sequences were highly conserved, indicating long-term persistence from dominant strains. Notably, EBV
819-404: A portal complex that allows entry and exit of DNA into the capsid. All herpesviruses are nuclear-replicating—the viral DNA is transcribed to mRNA within the infected cell's nucleus . Infection is initiated when a viral particle contacts a cell with specific types of receptor molecules on the cell surface . Following binding of viral envelope glycoproteins to cell membrane receptors,
910-463: A resting naïve B cell , EBV enters Latency III. The set of proteins and RNAs produced in Latency ;III transforms the B cell into a proliferating blast (also known as B cell activation). Later, the virus restricts its gene expression and enters Latency II. The more limited set of proteins and RNAs produced in Latency II induces the B cell to differentiate into
1001-528: A surgeon practicing in Uganda , in which Burkitt described the "endemic variant" (pediatric form) of the disease that now bears his name . In 1963, a specimen was sent from Uganda to Middlesex Hospital to be cultured. Virus particles were identified in the cultured cells, and the results were published in The Lancet in 1964 by Epstein, Achong, and Barr. Cell lines were sent to Werner and Gertrude Henle at
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#17327765578691092-570: A transcript starting at either the Cp or Wp promoters at the left end of the genome (in the conventional nomenclature). The genes are ordered EBNA-LP/EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1 within the genome. The initiation codon of the EBNA-LP coding region is created by an alternate splice of the nuclear protein transcript. In the absence of this initiation codon, EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1 will be expressed depending on which of these genes
1183-725: Is a compound containing carbohydrate (or glycan) covalently linked to protein. The carbohydrate may be in the form of a monosaccharide, disaccharide(s). oligosaccharide(s), polysaccharide(s), or their derivatives (e.g. sulfo- or phospho-substituted). One, a few, or many carbohydrate units may be present. Proteoglycans are a subclass of glycoproteins in which the carbohydrate units are polysaccharides that contain amino sugars. Such polysaccharides are also known as glycosaminoglycans. A variety of methods used in detection, purification, and structural analysis of glycoproteins are The glycosylation of proteins has an array of different applications from influencing cell to cell communication to changing
1274-474: Is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses . The family name is derived from the Greek word ἕρπειν ( herpein 'to creep'), referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster ( shingles ). In 1971,
1365-528: Is also associated with the childhood disorders of Alice in Wonderland syndrome and acute cerebellar ataxia and, by some evidence, higher risks of developing certain autoimmune diseases , especially dermatomyositis , systemic lupus erythematosus , rheumatoid arthritis , and Sjögren's syndrome . About 200,000 cancer cases globally per year are thought to be attributable to EBV. In 2022, a large study (population of 10 million over 20 years) suggested EBV as
1456-454: Is also associated with various non-malignant, premalignant , and malignant Epstein–Barr virus-associated lymphoproliferative diseases such as Burkitt lymphoma , hemophagocytic lymphohistiocytosis , and Hodgkin's lymphoma ; non-lymphoid malignancies such as gastric cancer and nasopharyngeal carcinoma ; and conditions associated with human immunodeficiency virus such as hairy leukoplakia and central nervous system lymphomas . The virus
1547-428: Is also tightly linked to many malignant diseases (cancers). Various vaccine formulations underwent testing in different animals or in humans. However, none of them were able to prevent EBV infection and no vaccine has been approved to date. Infectious mononucleosis ("mono" or "glandular fever"), a disease caused by the virus, is characterized by extreme fatigue, fever, sore throat, and swollen lymph nodes. The virus
1638-500: Is alternatively spliced into the transcript. EBV can be divided into two major types, EBV type 1 and EBV type 2. These two subtypes have different EBNA-3 genes. As a result, the two subtypes differ in their transforming capabilities and reactivation ability. Type 1 is dominant throughout most of the world, but the two types are equally prevalent in Africa . One can distinguish EBV type 1 from EBV type 2 by cutting
1729-643: Is an obstacle to development of prophylactic and therapeutic vaccines against EBV. Like other human herpesviruses Epstein–Barr might allow its own eradication via a course of the drug valaciclovir , but further research is needed to determine if eradication is actually achievable. Antiviral agents act by inhibiting viral DNA replication, but there is little evidence that they are effective against Epstein–Barr virus. Moreover, they are expensive, risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects . Herpesviridae#Human herpesvirus types See text Herpesviridae
1820-603: Is analyzed to elucidate molecular mechanisms of latency. The avian infectious laryngotracheitis virus is phylogenetically distant from these two viruses and serves to underline similarity and diversity within the Alphaherpesvirinae . Research is currently ongoing into a variety of side-effect or co-conditions related to the herpesviruses. These include: Glycoproteins Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate
1911-424: Is attached to the protein in a cotranslational or posttranslational modification . This process is known as glycosylation . Secreted extracellular proteins are often glycosylated. In proteins that have segments extending extracellularly, the extracellular segments are also often glycosylated. Glycoproteins are also often important integral membrane proteins , where they play a role in cell–cell interactions. It
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#17327765578692002-499: Is being studied to determine just how to induce immune destruction of latently infected B cells by use of either TPA or sodium butyrate . Unlike lytic replication, latency does not result in production of virions. Instead, the EBV genome circular DNA resides in the cell nucleus as an episome and is copied by host-cell DNA polymerase . It persists in the individual's memory B cells . Epigenetic changes such as DNA methylation and cellular chromatin constituents, suppress
2093-589: Is delayed to adolescence or adulthood, it can cause fatigue , fever , inflamed throat , swollen lymph nodes in the neck, enlarged spleen , swollen liver , or rash. Post-infectious chronic fatigue syndrome has also been associated with EBV infection. EBV has also been implicated in several other diseases, including Burkitt's lymphoma , hemophagocytic lymphohistiocytosis , Hodgkin's lymphoma , stomach cancer , nasopharyngeal carcinoma , multiple sclerosis , and lymphomatoid granulomatosis . Specifically, EBV infected B cells have been shown to reside within
2184-789: Is important to distinguish endoplasmic reticulum-based glycosylation of the secretory system from reversible cytosolic-nuclear glycosylation. Glycoproteins of the cytosol and nucleus can be modified through the reversible addition of a single GlcNAc residue that is considered reciprocal to phosphorylation and the functions of these are likely to be an additional regulatory mechanism that controls phosphorylation-based signalling. In contrast, classical secretory glycosylation can be structurally essential. For example, inhibition of asparagine-linked, i.e. N-linked, glycosylation can prevent proper glycoprotein folding and full inhibition can be toxic to an individual cell. In contrast, perturbation of glycan processing (enzymatic removal/addition of carbohydrate residues to
2275-472: Is known to happen in vivo , but what triggers it is not known precisely. In vitro , latent EBV in B cells can be reactivated by stimulating the B cell receptor, so it is likely reactivation in vivo takes place after latently infected B cells respond to unrelated infections. EBV infection of B lymphocytes leads to " immortalization " of these cells, meaning that the virus causes them to continue dividing indefinitely. Normally, cells have
2366-530: Is likely to have been secondary to its role in host-pathogen interactions. A famous example of this latter effect is the ABO blood group system . Though there are different types of glycoproteins, the most common are N -linked and O -linked glycoproteins. These two types of glycoproteins are distinguished by structural differences that give them their names. Glycoproteins vary greatly in composition, making many different compounds such as antibodies or hormones. Due to
2457-459: Is necessary for virus persistence, subsequent replication in epithelial cells, and release of infectious virus into saliva. EBV Latency III and II infections of B lymphocytes, Latency II infection of oral epithelial cells, and Latency II infection of NK- or T-cell can result in malignancies, marked by uniform EBV genome presence and gene expression. Latent EBV in B cells can be reactivated to switch to lytic replication . This
2548-728: Is often accompanied by emergence of nonspecific symptoms , such as low-grade fever, headache, sore throat, malaise , and rash, as well as clinical signs such as swollen or tender lymph nodes and immunological findings such as reduced levels of natural killer cells . In animal models, local trauma and system stress have been found to induce reactivation of latent herpesvirus infection. Cellular stressors like transient interruption of protein synthesis and hypoxia are also sufficient to induce viral reactivation. The three mammalian subfamilies – Alpha -, Beta - and Gamma - herpesviridae – arose approximately 180 to 220 mya . The major sublineages within these subfamilies were probably generated before
2639-515: Is the consequence of viral protein expression. EBNA-2, EBNA-3C, and LMP-1, are essential for transformation, whereas EBNA-LP and the EBERs are not. Following natural infection with EBV, the virus is thought to execute some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial absence of host immunity , the lytic cycle produces large numbers of virions to infect other (presumably) B-lymphocytes within
2730-450: Is through the reaction between a protected glycan and a protected Asparagine. Similarly, an O-linked glycoprotein can be formed through the addition of a glycosyl donor with a protected Serine or Threonine . These two methods are examples of natural linkage. However, there are also methods of unnatural linkages. Some methods include ligation and a reaction between a serine-derived sulfamidate and thiohexoses in water. Once this linkage
2821-548: Is to encode viral proteins that detain the newly formed MHC in the endoplasmic reticulum (ER). The MHC cannot reach the cell surface and therefore cannot activate the T cell response. The MHCs can also be targeted for destruction in the proteasome or lysosome . The ER protein TAP also plays a role in MHC down regulation. Viral proteins inhibit TAP preventing the MHC from picking up a viral antigen peptide. This prevents proper folding of
Epstein–Barr virus - Misplaced Pages Continue
2912-464: The 11th chromosome , specifically in the 11q23 region between the FAM55D gene and FAM55B, which EBNA-1 appears to have a high affinity for due to its DNA-binding domain having an interest in a specific palindromic repeat in this section of the genome. While the cause and exact mechanism for this is unknown, the byproduct results in errors and breakage of the chromosomal structure as cells stemming from
3003-455: The Children's Hospital of Philadelphia who developed serological markers. In 1967, a technician in their laboratory developed mononucleosis and they were able to compare a stored serum sample, showing that antibodies to the virus developed. In 1968, they discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related infections, and confirmed
3094-766: The International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections. Nine herpesvirus types are known to primarily infect humans, at least five of which are extremely widespread among most human populations, and which cause common diseases: herpes simplex 1 and 2 (HSV-1 and HSV-2, also known as HHV-1 and HHV-2; both of which can cause orolabial and genital herpes ), varicella zoster (or HHV-3;
3185-463: The capsid , which is itself wrapped in a protein layer called the tegument containing both viral proteins and viral mRNAs and a lipid bilayer membrane called the envelope . This whole particle is known as a virion . The structural components of a typical HSV virion are the Lipid bilayer envelope, Tegument, DNA, Glycoprotein spikes and Nucleocapsid. The four-component Herpes simplex virion encompasses
3276-481: The expression of later lytic genes. Immediate-early lytic gene products include BZLF1 (also known as Zta, EB1, associated with its product gene ZEBRA ) and BRLF1 (associated with its product gene Rta ). Early lytic gene products have many more functions, such as replication, metabolism, and blockade of antigen processing . Early lytic gene products include BNLF2 . Finally, late lytic gene products tend to be proteins with structural roles, such as VCA , which forms
3367-458: The EBV DNA are detected. Direct detection of EBV genome presence via polymerase chain reaction (PCR) is seldom done, as this method says nothing about the immune system's reaction to the virus. EBV viral load does not correlate well with clinical symptoms of infection. EBV causes infectious mononucleosis. Children infected with EBV have few symptoms or can appear asymptomatic, but when infection
3458-461: The MHC and therefore the MHC does not reach the cell surface. Below are the nine distinct viruses in this family known to cause disease in humans. In addition to the herpesviruses considered endemic in humans, some viruses associated primarily with animals may infect humans. These are zoonotic infections: In animal virology , the best known herpesviruses belong to the subfamily Alphaherpesvirinae . Research on pseudorabies virus (PrV),
3549-500: The S727 residue. Another one of the many ways in which herpes viruses evade the immune system is by down regulation of MHC I and MHC II . This is observed in almost every human herpesvirus. Down regulation of MHC I and MHC II can come about by many different mechanisms, most causing the MHC to be absent from the cell surface. As discussed above, one way is by a viral chemokine homolog such as IL-10. Another mechanism to down regulate MHCs
3640-418: The alphaherpesviruses may have been the earliest branch. The time of origin of the genus Iltovirus has been estimated to be 200 mya while those of the mardivirus and simplex genera have been estimated to be between 150 and 100 mya. Herpesviruses are known for their ability to establish lifelong infections. One way this is possible is through immune evasion. Herpesviruses have many different ways of evading
3731-542: The body is mucins , which are secreted in the mucus of the respiratory and digestive tracts. The sugars when attached to mucins give them considerable water-holding capacity and also make them resistant to proteolysis by digestive enzymes. Glycoproteins are important for white blood cell recognition. Examples of glycoproteins in the immune system are: H antigen of the ABO blood compatibility antigens. Other examples of glycoproteins include: Soluble glycoproteins often show
Epstein–Barr virus - Misplaced Pages Continue
3822-470: The brain lesions of multiple sclerosis patients, and a 2022 study of 10 million soldiers' historical blood samples showed that "Individuals who were not infected with the Epstein–Barr virus virtually never get multiple sclerosis. It's only after Epstein–Barr virus infection that the risk of multiple sclerosis jumps up by over 30 fold", and that only EBV of many infections had such a clear connection with
3913-414: The causative agent of Aujeszky's disease in pigs, has pioneered animal disease control with genetically modified vaccines. PrV is now extensively studied as a model for basic processes during lytic herpesvirus infection, and for unraveling molecular mechanisms of herpesvirus neurotropism, whereas bovine herpesvirus 1 , the causative agent of bovine infectious rhinotracheitis and pustular vulvovaginitis ,
4004-479: The cause of chickenpox and shingles ), Epstein–Barr (EBV or HHV-4; implicated in several diseases, including mononucleosis and some cancers), and human cytomegalovirus (HCMV or HHV-5). More than 90% of adults have been infected with at least one of these, and a latent form of the virus remains in almost all humans who have been infected. Other human herpesviruses are human herpesvirus 6A and 6B (HHV-6A and HHV-6B) and human herpesvirus 7 (HHV-7), which are
4095-444: The cell (and thus the host) indefinitely. While primary infection is often accompanied by a self-limited period of clinical illness, long-term latency is symptom-free. Chromatin dynamics regulate the transcription competency of entire herpes virus genomes. When the virus enters a cell, the cellular immune response is to protect the cell. The cell does so by wrapping the viral DNA around histones and condensing it into chromatin, causing
4186-483: The cell, causing a decrease in drug effectiveness. Therefore, being able to inhibit this behavior would decrease P-glycoprotein interference in drug delivery, making this an important topic in drug discovery. For example, P-Glycoprotein causes a decrease in anti-cancer drug accumulation within tumor cells, limiting the effectiveness of chemotherapies used to treat cancer. Hormones that are glycoproteins include: Quoting from recommendations for IUPAC: A glycoprotein
4277-447: The cell-mediated immune response and natural killer cell response, respectively. The similarities between hIL-10 and cmvIL-10 may be explained by the fact that hIL-10 and cmvIL-10 both use the same cell surface receptor, the hIL-10 receptor. One difference in the function of hIL-10 and cmvIL-10 is that hIL-10 causes human peripheral blood mononuclear cells ( PBMC ) to both increase and decrease in proliferation whereas cmvIL-10 only causes
4368-916: The disease. Additional diseases that have been linked to EBV include Gianotti–Crosti syndrome , erythema multiforme , acute genital ulcers, and oral hairy leukoplakia . The viral infection is also associated with, and often contributes to the development of, a wide range of non-malignant lymphoproliferative diseases such as severe hypersensitivity mosquito bite allergy reactions, Epstein–Barr virus-positive mucocutaneous ulcers , and hydroa vacciniforme as well as malignant lymphoproliferative diseases such as Epstein–Barr virus-positive Burkitt lymphoma , Epstein–Barr virus-positive Hodgkin lymphoma , and primary effusion lymphoma . The Epstein–Barr virus has been implicated in disorders related to alpha-synuclein aggregation (e.g. Parkinson's disease , dementia with Lewy bodies , and multiple system atrophy ). It has been found that EBNA1 may induce chromosomal breakage in
4459-496: The double-stranded DNA genome into an icosahedral nucleocapsid. There is tegument around. Tegument contains filaments, each 7 nm wide. It is an amorphous layer with some structured regions. Finally, it is covered with a lipoprotein envelope. There are spikes made of glycoprotein protruding from each virion. These can expand the diameter of the virus to 225 nm. The diameters of virions without spikes are around 186 nm. There are at least two unglycosylated membrane proteins in
4550-553: The eight human herpesviruses). Although many viruses are assumed to have this property during infection of their natural hosts, there is not an easily managed system for studying this part of the viral lifecycle. Genomic studies of EBV have been able to explore lytic reactivation and regulation of the latent viral episome. Although under active research, an Epstein–Barr virus vaccine is not yet available. The development of an effective vaccine could prevent up to 200,000 cancers globally per year. The absence of effective animal models
4641-527: The etiological agents for Roseola , and HHV-8 (also known as KSHV) which is responsible for causing Kaposi's sarcoma-associated herpesvirus . HHV here stands for "Human Herpesvirus". In total, more than 130 herpesviruses are known, some of them from mammals, birds, fish, reptiles, amphibians, and molluscs. Among the animal herpesviruses are pseudorabies virus causing Aujeszky's disease in pigs, and bovine herpesvirus 1 causing bovine infectious rhinotracheitis and pustular vulvovaginitis . Additionally,
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#17327765578694732-420: The glycan), which occurs in both the endoplasmic reticulum and Golgi apparatus , is dispensable for isolated cells (as evidenced by survival with glycosides inhibitors) but can lead to human disease (congenital disorders of glycosylation) and can be lethal in animal models. It is therefore likely that the fine processing of glycans is important for endogenous functionality, such as cell trafficking, but that this
4823-423: The highly stable EBNA-1 gene found across all stages of EBV infection is unaffected. Specific inhibitors (to the pathways) suggest that Ras/MEK/MAPK pathway contributes to EBV lytic infection though BZLF1 and PI3-K pathway through BRLF1, the latter completely abrogating the ability of a BRLF1 adenovirus vector to induce the lytic form of EBV infection. Additionally, the activation of some genes but not others
4914-580: The host cell . In July 2020, a team of researchers reported the first complete atomic model of the nucleocapsid of the virus. This "first complete atomic model [includes] the icosahedral capsid, the capsid-associated tegument complex (CATC) and the dodecameric portal—the viral genome translocation apparatus." The term viral tropism refers to which cell types that EBV infects. EBV can infect different cell types, including B cells and epithelial cells . The viral three-part glycoprotein complexes of gHgL gp42 mediate B cell membrane fusion; although
5005-535: The host cell and so are largely 'self'. Over time, some patients can evolve antibodies to recognise the HIV glycans and almost all so-called 'broadly neutralising antibodies (bnAbs) recognise some glycans. This is possible mainly because the unusually high density of glycans hinders normal glycan maturation and they are therefore trapped in the premature, high-mannose, state. This provides a window for immune recognition. In addition, as these glycans are much less variable than
5096-514: The host. The latent programs reprogram and subvert infected B-lymphocytes to proliferate and bring infected cells to the sites at which the virus presumably persists. Eventually, when host immunity develops, the virus persists by turning off most (or possibly all) of its genes and only occasionally reactivates and produces progeny virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression. The manipulation of
5187-608: The human body's epigenetics by EBV can alter the genome of the cell to leave oncogenic phenotypes. As a result, the modification by the EBV increases the hosts likelihood of developing EBV related cancer. EBV related cancers are unique in that they are frequent to making epigenetic changes but are less likely to mutate. The site of persistence of EBV may be bone marrow . EBV-positive patients who have had their own bone marrow replaced with bone marrow from an EBV-negative donor are found to be EBV-negative after transplantation . All EBV nuclear proteins are produced by alternative splicing of
5278-460: The immune system. One such way is by encoding a protein mimicking human interleukin 10 (hIL-10) and another is by downregulation of the major histocompatibility complex II (MHC II) in infected cells. Research conducted on cytomegalovirus (CMV) indicates that the viral human IL-10 homolog, cmvIL-10, is important in inhibiting pro-inflammatory cytokine synthesis. The cmvIL-10 protein has 27% identity with hIL-10 and only one conserved residue out of
5369-638: The leading cause of multiple sclerosis , with a recent EBV infection causing a 32-fold increase in the risk of developing multiple sclerosis. Infection with EBV occurs by the oral transfer of saliva and genital secretions. Most people become infected with EBV and gain adaptive immunity . In the United States, about half of all five-year-old children and about 90% of adults have evidence of previous infection. Infants become susceptible to EBV as soon as maternal antibody protection disappears. Many children who become infected with EBV display no symptoms or
5460-435: The line of the tainted genome undergo mitosis . Since genes in this area have been implicated in leukemia and is home to a tumor suppressor gene that is modified or not present in most tumor gene expression, it's been hypothesized that breakage in this area is the main culprit behind the cancers that EBV increases the chance of. The breakage is also dose-dependent, a person with a latent infection will have less breakage than
5551-495: The link between the virus and infectious mononucleosis. As a relatively complex virus, EBV is not yet fully understood. Laboratories around the world continue to study the virus and develop new ways to treat the diseases it causes. One popular way of studying EBV in vitro is to use bacterial artificial chromosomes . Epstein–Barr virus can be maintained and manipulated in the laboratory in continual latency (a property shared with Kaposi's sarcoma-associated herpesvirus , another of
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#17327765578695642-491: The majority of the viral genes in latently infected cells. Only a portion of EBV's genes are expressed , which support the latent state of the virus. Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist within B cells and epithelial cells , but different latency programs are possible in the two types of cell. EBV can exhibit one of three latency programs: Latency I, Latency II, or Latency III. Each latency program leads to
5733-413: The mammalian radiation of 80 to 60 mya. Speciations within sublineages took place in the last 80 million years probably with a major component of cospeciation with host lineages. All the currently known bird and reptile species are alphaherpesviruses. Although the branching order of the herpes viruses has not yet been resolved, because herpes viruses and their hosts tend to coevolve this is suggestive that
5824-469: The most common cell line used for recombinant glycoprotein production is the Chinese hamster ovary line. However, as technologies develop, the most promising cell lines for recombinant glycoprotein production are human cell lines. The formation of the link between the glycan and the protein is key element of the synthesis of glycoproteins. The most common method of glycosylation of N-linked glycoproteins
5915-706: The most common. Monosaccharides commonly found in eukaryotic glycoproteins include: The sugar group(s) can assist in protein folding , improve proteins' stability and are involved in cell signalling. The critical structural element of all glycoproteins is having oligosaccharides bonded covalently to a protein. There are 10 common monosaccharides in mammalian glycans including: glucose (Glc), fucose (Fuc), xylose (Xyl), mannose (Man), galactose (Gal), N- acetylglucosamine (GlcNAc), glucuronic acid (GlcA), iduronic acid (IdoA), N-acetylgalactosamine (GalNAc), sialic acid , and 5- N-acetylneuraminic acid (Neu5Ac). These glycans link themselves to specific areas of
6006-486: The nine amino acids that make up the functional site for cytokine synthesis inhibition on hIL-10. There is, however, much similarity in the functions of hIL-10 and cmvIL-10. Both have been shown to down regulate IFN-γ , IL-1α , GM-CSF , IL-6 and TNF-α , which are all pro-inflammatory cytokines. They have also been shown to play a role in downregulating MHC I and MHC II and up regulating HLA-G (non-classical MHC I). These two events allow for immune evasion by suppressing
6097-478: The outer envelope of the virion. There are also 11 glycoproteins. These are gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL and gM. Tegument contains 26 proteins. They have duties such as capsid transport to the nucleus and other organelles, activation of early gene transcription, and mRNA degradation. The icosahedral nucleocapsid is similar to that of tailed bacteriophage in the order Caudovirales . This capsid has 161 capsomers consisting of 150 hexons and 11 pentons, as well as
6188-429: The production of a limited, distinct set of viral proteins and viral RNAs . Also, a program is postulated in which all viral protein expression is shut off (Latency 0). Within B cells, all three latency programs are possible. EBV latency within B cells usually progresses from Latency III to Latency II to Latency I. Each stage of latency uniquely influences B cell behavior. Upon infecting
6279-471: The production of the protein. Glycosylation is a process that roughly half of all human proteins undergo and heavily influences the properties and functions of the protein. Within the cell, glycosylation occurs in the endoplasmic reticulum . There are several techniques for the assembly of glycoproteins. One technique utilizes recombination . The first consideration for this method is the choice of host, as there are many different factors that can influence
6370-488: The protein amino acid chain. The two most common linkages in glycoproteins are N -linked and O -linked glycoproteins. An N -linked glycoprotein has glycan bonds to the nitrogen containing an asparagine amino acid within the protein sequence. An O -linked glycoprotein has the sugar is bonded to an oxygen atom of a serine or threonine amino acid in the protein. Glycoprotein size and composition can vary largely, with carbohydrate composition ranges from 1% to 70% of
6461-487: The purposes of this field of study is to determine which proteins are glycosylated and where in the amino acid sequence the glycosylation occurs. Historically, mass spectrometry has been used to identify the structure of glycoproteins and characterize the carbohydrate chains attached. The unique interaction between the oligosaccharide chains have different applications. First, it aids in quality control by identifying misfolded proteins. The oligosaccharide chains also change
6552-474: The rest of their life. The virus is about 122–180 nm in diameter and is composed of a double helix of deoxyribonucleic acid (DNA) which contains about 172,000 base pairs encoding 85 genes . The DNA is surrounded by a protein nucleocapsid , which is surrounded by a tegument made of protein, which in turn is surrounded by an envelope containing both lipids and surface projections of glycoproteins , which are essential to infection of
6643-405: The solubility and polarity of the proteins that they are bonded to. For example, if the oligosaccharide chains are negatively charged, with enough density around the protein, they can repulse proteolytic enzymes away from the bonded protein. The diversity in interactions lends itself to different types of glycoproteins with different structures and functions. One example of glycoproteins found in
6734-505: The species Iguanid herpesvirus 2 is currently unassigned to a genus and subfamily. See Herpesvirales#Taxonomy for information on taxonomic history, phylogenetic research, and the nomenclatural system. All members of the Herpesviridae share a common structure; a relatively large, monopartite, double-stranded, linear DNA genome encoding 100–200 genes encased within an icosahedral protein cage (with T=16 symmetry) called
6825-493: The success of glycoprotein recombination such as cost, the host environment, the efficacy of the process, and other considerations. Some examples of host cells include E. coli, yeast, plant cells, insect cells, and mammalian cells. Of these options, mammalian cells are the most common because their use does not face the same challenges that other host cells do such as different glycan structures, shorter half life, and potential unwanted immune responses in humans. Of mammalian cells,
6916-404: The symptoms are indistinguishable from the other mild, brief illnesses of childhood. When infection occurs during adolescence or young adulthood, it causes infectious mononucleosis 35 to 50% of the time. EBV infects B cells of the immune system and epithelial cells . Once EBV's initial lytic infection is brought under control, EBV latency persists in the individual's memory B cells for
7007-403: The thermal stability and the folding of proteins. Due to the unique abilities of glycoproteins, they can be used in many therapies. By understanding glycoproteins and their synthesis, they can be made to treat cancer, Crohn's Disease , high cholesterol, and more. The process of glycosylation (binding a carbohydrate to a protein) is a post-translational modification , meaning it happens after
7098-543: The total mass of the glycoprotein. Within the cell, they appear in the blood, the extracellular matrix , or on the outer surface of the plasma membrane, and make up a large portion of the proteins secreted by eukaryotic cells. They are very broad in their applications and can function as a variety of chemicals from antibodies to hormones. Glycomics is the study of the carbohydrate components of cells. Though not exclusive to glycoproteins, it can reveal more information about different glycoproteins and their structure. One of
7189-518: The two-part complexes of gHgL mediate epithelial cell membrane fusion. EBV that are made in the B cells have low numbers of gHgLgp42 complexes, because these three-part complexes interact with Human-leukocyte-antigen class II molecules present in B cells in the endoplasmic reticulum and are degraded. In contrast, EBV from epithelial cells are rich in the three-part complexes because these cells do not normally contain HLA class II molecules. As
7280-402: The underlying protein, they have emerged as promising targets for vaccine design. P-glycoproteins are critical for antitumor research due to its ability block the effects of antitumor drugs. P-glycoprotein, or multidrug transporter (MDR1), is a type of ABC transporter that transports compounds out of cells. This transportation of compounds out of cells includes drugs made to be delivered to
7371-451: The viral capsid . Other late lytic gene products, such as BCRF1, help EBV evade the immune system. EGCG , a polyphenol in green tea , has shown in a study to inhibit EBV spontaneous lytic infection at the DNA, gene transcription, and protein levels in a time- and dose-dependent manner; the expression of EBV lytic genes Zta, Rta , and early antigen complex EA-D (induced by Rta ), however,
7462-578: The viral envelope with the cell membrane, allowing EBV to enter the B cell. Human CD35, also known as complement receptor 1 (CR1), is an additional attachment factor for gp350 / 220, and can provide a route for entry of EBV into CD21-negative cells, including immature B-cells. EBV infection downregulates expression of CD35. To enter epithelial cells, viral protein BMRF-2 interacts with cellular β1 integrins . Then, viral protein gH/gL interacts with cellular αvβ6 / αvβ8 integrins. This triggers fusion of
7553-682: The viral envelope with the epithelial cell membrane, allowing EBV to enter the epithelial cell. Unlike B-cell entry, epithelial-cell entry is actually impeded by viral glycoprotein gp42. Once EBV enters the cell, the viral capsid dissolves and the viral genome is transported to the cell nucleus . The lytic cycle , or productive infection, results in the production of infectious virions . EBV can undergo lytic replication in both B cells and epithelial cells. In B cells, lytic replication normally only takes place after reactivation from latency . In epithelial cells, lytic replication often directly follows viral entry . For lytic replication to occur,
7644-478: The viral genome must be linear. The latent EBV genome is circular, so it must linearize in the process of lytic reactivation. During lytic replication, viral DNA polymerase is responsible for copying the viral genome. This contrasts with latency, in which host-cell DNA polymerase copies the viral genome. Lytic gene products are produced in three consecutive stages: immediate-early, early, and late. Immediate-early lytic gene products act as transactivators , enhancing
7735-494: The viral genome with a restriction enzyme and comparing the resulting digestion patterns by gel electrophoresis . Epstein–Barr virus-encoded small RNAs (EBERs) are by far the most abundant EBV products transcribed in cells infected by EBV. They are commonly used as targets for the detection of EBV in histological tissues. Clinically, the most common way to detect the presence of EBV is enzyme-linked immuno sorbent assay (ELISA). Antibodies (IgM and IgG) to proteins encoded by
7826-419: The virion is internalized and dismantled, allowing viral DNA to migrate to the cell nucleus. Within the nucleus, replication of viral DNA and transcription of viral genes occurs. During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latency-associated transcript (LAT) accumulate, instead. In this fashion, the virus can persist in
7917-612: The virus to become dormant, or latent. If cells are unsuccessful and the chromatin is loosely bundled, the viral DNA is still accessible. The viral particles can turn on their genes and replicate using cellular machinery to reactivate, starting a lytic infection. Reactivation of latent viruses has been implicated in a number of diseases (e.g. shingles , pityriasis rosea ). Following activation, transcription of viral genes transitions from LAT to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads to cell death . Clinically, lytic activation
8008-445: The virus's dynamic nature within the host and its possible contribution to the progression of EBV-associated cancers. The Epstein–Barr virus was named after M.A. Epstein and Yvonne Barr , who discovered the virus together with Bert Achong . In 1961, Epstein, a pathologist and expert electron microscopist , attended a lecture on "The commonest children's cancer in tropical Africa—a hitherto unrecognised syndrome" by D. P. Burkitt ,
8099-400: The wide array of functions within the body, interest in glycoprotein synthesis for medical use has increased. There are now several methods to synthesize glycoproteins, including recombination and glycosylation of proteins. Glycosylation is also known to occur on nucleo cytoplasmic proteins in the form of O -GlcNAc . There are several types of glycosylation, although the first two are
8190-571: Was also found to phosphorylate Stat3. PI3K inhibition, unlike JAK inhibition, did have a significant impact on cytokine synthesis. The difference between PI3K and JAK in Stat3 phosphorylation is that PI3K phosphorylates Stat3 on the S727 residue whereas JAK phosphorylates Stat3 on the Y705 residue. This difference in phosphorylation positions seems to be the key factor in Stat3 activation leading to inhibition of pro-inflammatory cytokine synthesis. In fact, when
8281-542: Was found to integrate into the host genome in cases of malignancies, including mantle cell lymphoma, where a significant integration event was observed involving the EBV LMP-1 gene and chromosome 17. This integration likely occurred via microhomology-mediated end joining, suggesting a potential mechanism through which EBV may influence tumorigenesis. Moreover, instances of high viral loads and accompanying genetic diversity were noted in patients with active disease, underscoring
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