| Epstein–Barr virus | |
|---|---|
 | |
| Electron micrograph of two Epstein–Barr virions (viral particles) showing roundcapsids loosely surrounded by the membraneenvelope | |
Virus classification | |
| (unranked): | Virus |
| Realm: | Duplodnaviria |
| Kingdom: | Heunggongvirae |
| Phylum: | Peploviricota |
| Class: | Herviviricetes |
| Order: | Herpesvirales |
| Family: | Orthoherpesviridae |
| Genus: | Lymphocryptovirus |
| Species: | Lymphocryptovirus humangamma4 |
| Synonyms[1] | |
| |
TheEpstein–Barr virus (EBV) is one of the nine knownhuman herpesvirus types in theherpes family, and is one of the most commonviruses in humans. EBV is adouble-stranded DNA virus and is also calledhuman herpesvirus 4 (HHV-4).[2] Epstein–Barr virus (EBV) is the first identifiedoncogenic virus, or a virus that can causecancer. EBV establishes permanent infection in humans. It causesinfectious mononucleosis and is also tightly linked to manymalignant diseases (cancers). Variousvaccine 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.[3]
Infectious mononucleosis ("mono" or "glandular fever"), is characterized by extreme fatigue, fever, sore throat, and swollen lymph nodes. Epstein–Barr virus is also associated with various non-malignant,premalignant, and malignantEpstein–Barr virus-associated lymphoproliferative diseases such asBurkitt lymphoma,hemophagocytic lymphohistiocytosis,[4] andHodgkin's lymphoma; non-lymphoid malignancies such asgastric cancer andnasopharyngeal carcinoma; and conditions associated withhuman immunodeficiency virus such ashairy leukoplakia andcentral nervous systemlymphomas.[5][6] The virus is also associated with the childhood disorders ofAlice in Wonderland syndrome[7] andacute cerebellar ataxia[8] and, by some evidence, higher risks of developing certainautoimmune diseases,[9] especiallydermatomyositis,systemic lupus erythematosus,rheumatoid arthritis, andSjögren's syndrome.[10][11] About 200,000 cancer cases globally per year are thought to be attributable to EBV.[12][13] In 2022, a large study (population of 10 million over 20 years) suggested EBV as the leading cause ofmultiple sclerosis, with a recent EBV infection causing a32-fold increase in the risk of developing multiple sclerosis.[14][15][16][17][18]
Infection with EBV occurs by the oral transfer ofsaliva[19] and genital secretions. Most people become infected with EBV and gainadaptive immunity. In the United States, about half of all five-year-old children and about 90% of adults have evidence of previous infection.[20] Infants become susceptible to EBV as soon asmaternal antibody protection disappears. Many children who become infected with EBV display no symptoms or the symptoms are indistinguishable from the other mild, brief illnesses of childhood.[21] When infection occurs during adolescence or young adulthood, it causes infectious mononucleosis 35 to 50% of the time.[22]
EBV infectsB cells of the immune system andepithelial cells. Once EBV's initiallytic infection is brought under control, EBVlatency persists in the individual'smemory B cells for the rest of their life.[19][23][24]
Thevirus is about 122–180 nm in diameter and is composed ofa double helix ofdeoxyribonucleic acid (DNA) which contains about 172,000 base pairs encoding 85 genes.[19] The DNA is surrounded by a proteinnucleocapsid, which is surrounded by ategument made of protein, which in turn is surrounded by anenvelope containing bothlipids and surface projections ofglycoproteins, which are essential toinfection of the host cell.[25] 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."[26][27]
The termviral tropism refers to which cell types that EBV infects. EBV can infect different cell types, includingB cells andepithelial cells.[28]
The viral three-part glycoprotein complexes ofgHgL gp42 mediate B cell membrane fusion; although 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 withHuman-leukocyte-antigenclass 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 containHLA class II molecules. As 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 thegp42 portion are able to bind to human B cells, but unable to infect.[29]
EBV can infect both B cells and epithelial cells. The mechanisms for entering these two cells are different.
To enter B cells, viralglycoproteingp350 binds to cellular receptorCD21 (also known as CR2).[30] Then, viral glycoprotein gp42 interacts with cellularMHC class II molecules. This triggersfusion of the viral envelope with the cell membrane, allowing EBV to enter the B cell.[25] Human CD35, also known ascomplement 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.[31]
To enter epithelial cells, viral protein BMRF-2 interacts with cellular β1integrins. Then, viral protein gH/gL interacts with cellularαvβ6/αvβ8 integrins. This triggersfusion of the viral envelope with the epithelial cell membrane, allowing EBV to enter the epithelial cell.[25] Unlike B-cell entry, epithelial-cell entry is actually impeded by viral glycoprotein gp42.[30]
Once EBV enters the cell, the viral capsid dissolves and the viral genome is transported to thecell nucleus.[32]
Thelytic cycle, or productive infection, results in the production of infectiousvirions. EBV can undergo lytic replication in both B cells and epithelial cells. In B cells, lytic replication normally only takes place after reactivation fromlatency. In epithelial cells, lytic replication often directly followsviral entry.[25]
For lytic replication to occur, 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, viralDNA polymerase is responsible for copying the viral genome. This contrasts with latency, in which host-cell DNA polymerase copies the viral genome.[25]
Lytic gene products are produced in three consecutive stages: immediate-early, early, and late.[25]Immediate-early lytic gene products act astransactivators, enhancing theexpression of later lytic genes. Immediate-early lytic gene products includeBZLF1 (also known as Zta, EB1, associated with its product geneZEBRA) andBRLF1 (associated with its product geneRta).[25]Early lytic gene products have many more functions, such as replication, metabolism, and blockade ofantigen processing. Early lytic gene products includeBNLF2.[25]Finally, late lytic gene products tend to be proteins with structural roles, such asVCA, which forms the viralcapsid. Other late lytic gene products, such as BCRF1, help EBV evade the immune system.[25]
EGCG, apolyphenol ingreen tea, has shown in a study to inhibit EBV spontaneous lytic infection at the DNA, gene transcription, and protein levels in a time- anddose-dependent manner; the expression of EBV lytic genes Zta, Rta, and early antigen complex EA-D (induced byRta), however, the highly stableEBNA-1 gene found across all stages of EBV infection is unaffected.[33] Specific inhibitors (to the pathways) suggest thatRas/MEK/MAPK pathway contributes to EBV lytic infection though BZLF1 andPI3-K pathway through BRLF1, the latter completely abrogating the ability of a BRLF1adenovirus vector to induce the lytic form of EBV infection.[33] Additionally, the activation of some genes but not others is being studied to determine just how to induce immune destruction of latently infected B cells by use of eitherTPA orsodium butyrate.[33]
Unlike lytic replication,latency does not result in production of virions.[25]Instead, the EBV genome circular DNA resides in thecell nucleus as anepisome and is copied by host-cellDNA polymerase.[25] It persists in the individual'smemory B cells.[19][24] Epigenetic changes such as DNAmethylation and cellularchromatin constituents, suppress the majority of the viral genes in latently infected cells.[34] Only a portion of EBV's genes areexpressed, which support the latent state of the virus.[34][19][35]Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist withinB cells andepithelial cells, but different latency programs are possible in the two types of cell.[36][37]
EBV can exhibit one of three latency programs: Latency I, Latency II, or Latency III. Each latency program leads to the production of a limited, distinct set of viralproteins and viralRNAs.[38][39]
| Gene Expressed | EBNA-1 | EBNA-2 | EBNA-3A | EBNA-3B | EBNA-3C | EBNA-LP | LMP1 | LMP-2A | LMP-2B | EBER |
|---|---|---|---|---|---|---|---|---|---|---|
| Product | Protein | Protein | Protein | Protein | Protein | Protein | Protein | Protein | Protein | ncRNAs |
| Latency I | + | – | – | – | – | – | – | – | – | + |
| Latency II | + | – | – | – | – | + | + | + | + | + |
| Latency III | + | + | + | + | + | + | + | + | + | + |
Also, a program is postulated in which all viral protein expression is shut off (Latency 0).[40]
Within B cells, all three latency programs are possible.[19] 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.[19] Upon infecting a restingnaïve 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).[19][25] 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 amemory B cell.[19][25] 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.[19][25]
Within epithelial cells, only Latency II is possible.[41]
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 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.[42]
Latent EBV in B cells can be reactivated to switch tolytic replication. This is known to happenin 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 reactivationin vivo takes place after latently infected B cells respond to unrelated infections.[25]
EBV infection of B lymphocytes leads to "immortalization" of these cells, meaning that the virus causes them to continue dividing indefinitely. Normally, cells have 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.[43]
When EBV infects B cellsin vitro,lymphoblastoid cell lines eventually emerge that are capable of indefinite growth. The growth transformation of these cell lines is the consequence of viral protein expression.[44]
EBNA-2, EBNA-3C, and LMP-1, are essential for transformation, whereas EBNA-LP and the EBERs are not.[45]
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 hostimmunity, the lytic cycle produces large numbers of virions to infect other (presumably) B-lymphocytes within 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 the human body's epigenetics by EBV can alter the genome of the cell to leave oncogenic phenotypes.[46] As a result, the modification by the EBV increases the hosts likelihood of developing EBV related cancer.[47] EBV related cancers are unique in that they are frequent to making epigenetic changes but are less likely to mutate.[48]
The site of persistence of EBV may bebone 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 aftertransplantation.[49]
All EBV nuclear proteins are produced by alternative splicing of a transcript starting at either the Cp or Wp promoters at the left end of thegenome (in the conventional nomenclature). The genes are orderedEBNA-LP/EBNA-2/EBNA-3A/EBNA-3B/EBNA-3C/EBNA-1 within the genome.
The initiationcodon 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 is alternatively spliced into the transcript.
| Protein/gene/antigen | Stage | Description |
|---|---|---|
| EBNA-1 | latent+lytic | EBNA-1 protein binds to a replication origin (oriP) within the viral genome and mediates replication and partitioning of the episome during division of the host cell. It is the only viral protein expressed during group I latency. |
| EBNA-2 | latent+lytic | EBNA-2 is the main viraltransactivator. |
| EBNA-3 | latent+lytic | These genes also bind the hostRBP-Jκ protein. |
| LMP-1 | latent | LMP-1 is a six-spantransmembrane protein that is also essential for EBV-mediated growth transformation. |
| LMP-2 | latent | LMP-2A/LMP-2B are transmembrane proteins that act to blocktyrosine kinase signaling. |
| EBER | latent | EBER-1/EBER-2 are small nuclear RNAs, which bind to certain nucleoprotein particles, enabling binding to PKR (dsRNA-dependent serin/threonin protein kinase), thus inhibiting its function. EBERs are by far the most abundant EBV products transcribed in EBV-infected cells. They are commonly used as targets for the detection of EBV in histological tissues.[50] ER-particles also induce the production of IL-10, which enhances growth and inhibits cytotoxic T cells. |
| v-snoRNA1 | latent | Epstein–Barr virus snoRNA1 is a box CD-snoRNA generated by the virus during latency. V-snoRNA1 may act as a miRNA-like precursor that is processed into 24 nucleotide sized RNA fragments that target the 3'UTR of viral DNA polymerase mRNA.[39] |
| ebv-sisRNA | latent | Ebv-sisRNA-1 is a stable intronic sequence RNA generated during latency program III. After theEBERs, it is the third-most abundant small RNA produced by the virus during this program.[51] |
| miRNAs | latent | EBV microRNAs are encoded by two transcripts, one set in theBART gene and one set near the BHRF1 cluster. The threeBHRF1 pri-miRNAS (generating four miRNAs) are expressed during type III latency, whereas the large cluster ofBART miRNAs (up to 20 miRNAs) are expressed highly during type II latency and only modestly during type I and II latency.[52] The previous reference also gives an account of the known functions of these miRNAs. |
| EBV-EA | lytic | early antigen |
| EBV-MA | lytic | membrane antigen |
| EBV-VCA | lytic | viral capsid antigen |
| EBV-AN | lytic | alkaline nuclease[53] |
EBV can be divided into two major types, EBV type 1 and EBV type 2. These two subtypes have differentEBNA-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 inAfrica. One can distinguish EBV type 1 from EBV type 2 by cutting the viral genome with arestriction enzyme and comparing the resulting digestion patterns bygel electrophoresis.[25]
| Typical interpretation | VCA-IgG | VCA-IgM | EA | EBNA |
|---|---|---|---|---|
| Never infected | – | – | – | – |
| Acute infection (IM) | + | + | +/− | – |
| Acute or recent infection | + | +/− | + | +/− |
| Recent past infection | + | – | +/− | + |
| Distant past infection | + | – | – | + |
| Chronic infection/reactivation | + | – | + | +/− |
![[icon]](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aWiki_letter_w_cropped.svg) | This sectionneeds expansion. You can help byadding to it.(March 2022) |
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.[50]
Clinically, the most common way to detect the presence of EBV isenzyme-linked immuno sorbent assay (ELISA).Antibodies (IgM and IgG) toproteins encoded by the EBV DNA are detected.[54] Direct detection of EBV genome presence viapolymerase 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.[55]
EBV causes infectious mononucleosis.[56] Children infected with EBV have few symptoms or can appear asymptomatic, but when infection is delayed to adolescence or adulthood, it can causefatigue,fever,inflamed throat,swollenlymph nodes in the neck,enlarged spleen,swollen liver, or rash.[20] Post-infectiouschronic fatigue syndrome has also been associated with EBV infection.[57][58]
EBV has also been implicated in several other diseases, includingBurkitt's lymphoma,[59]hemophagocytic lymphohistiocytosis,[60]Hodgkin's lymphoma,[61]stomach cancer,[12][62]nasopharyngeal carcinoma,[63]multiple sclerosis,[15][16][64][17] andlymphomatoid granulomatosis.[65]
EBV infected B cells have been shown to reside within the brain lesions ofmultiple sclerosis patients,[17] 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 the disease.[66]
Additional diseases that have been linked to EBV includeGianotti–Crosti syndrome,erythema multiforme, acute genital ulcers, andoral hairy leukoplakia.[67] The viral infection is also associated with, and often contributes to the development of, a wide range of non-malignantlymphoproliferative diseases such as severe hypersensitivitymosquito bite allergy reactions,[68]Epstein–Barr virus-positive mucocutaneous ulcers, andhydroa vacciniforme as well as malignant lymphoproliferative diseases such asEpstein–Barr virus-positive Burkitt lymphoma,[69]Epstein–Barr virus-positive Hodgkin lymphoma,[70] andprimary effusion lymphoma.[71]
The Epstein–Barr virus has been implicated in disorders related toalpha-synuclein aggregation (e.g.Parkinson's disease,dementia with Lewy bodies, andmultiple system atrophy).[72]
It has been found thatEBNA1 may induce chromosomal breakage in the11th chromosome, specifically in the 11q23 region between the FAM55D gene and FAM55B, which EBNA-1 appears to have a high affinity for due to itsDNA-binding domain having an interest in a specificpalindromic repeat in this section of the genome.[73] 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 the line of the tainted genome undergomitosis. Since genes in this area have been implicated inleukemia and is home to atumor 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 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 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 the virus's dynamic nature within the host and its possible contribution to the progression of EBV-associated cancers.[74]
The Epstein–Barr virus was named afterM.A. Epstein andYvonne Barr, who discovered the virus together withBert Achong.[75][76] In 1961, Epstein, apathologist and expertelectron microscopist, attended a lecture on "The commonest children's cancer in tropical Africa—a hitherto unrecognised syndrome" byD. P. Burkitt, a surgeon practicing inUganda, in which Burkitt described the "endemic variant" (pediatric form) of the disease thatnow bears his name. In 1963, a specimen was sent from Uganda toMiddlesex Hospital to be cultured. Virus particles were identified in the cultured cells, and the results were published inThe Lancet in 1964 by Epstein, Achong, and Barr.[76][77] Cell lines were sent toWerner and Gertrude Henle at theChildren's Hospital of Philadelphia who developedserological markers.[78] In 1967, a technician in their laboratory developed mononucleosis and they were able to compare a stored serum sample, showing thatantibodies to the virus developed.[77][79][80] In 1968, they discovered that EBV can directlyimmortalize B cells after infection,[43] mimicking some forms of EBV-related infections,[78] and confirmed the link between the virus and infectious mononucleosis.[81]
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 EBVin vitro is to usebacterial artificial chromosomes.[82] Epstein–Barr virus can be maintained and manipulated in the laboratory in continual latency (a property shared withKaposi's sarcoma-associated herpesvirus, another of 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.[83]
Although under active research, anEpstein–Barr virus vaccine is not yet available. The development of an effective vaccine could prevent up to 200,000 cancers globally per year.[12][13] The absence of effective animal models is an obstacle to development of prophylactic and therapeutic vaccines against EBV.[24]
It is possible, in theory, that a prolonged use ofvalaciclovir, an antiviral drug approved to treatherpes simplex orherpes zoster, might lead to Epstein–Barr eradication, but such theory was not confirmed by any study.[46] 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 unpleasantside effects.[47]
