Epstein–Barr virus

The Epstein–Barr virus (EBV) 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 and is also called human herpesvirus 4 (HHV-4).<ref name=pmid-32847820>Template:Cite journal</ref> 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 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.<ref>Urgency and necessity of Epstein–Barr virus prophylactic vaccines. 2022. npj Vaccines. 7/1. L. Zhong, C. Krummenacher, W. Zhang, J. Hong, Q. Feng, Y. Chen, et al. doi: 10.1038/s41541-022-00587-6.</ref>

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 malignant Epstein–Barr virus-associated lymphoproliferative diseases such as Burkitt lymphoma, hemophagocytic lymphohistiocytosis,<ref name=pmid-29885408>Template:Cite journal</ref> 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.<ref name=pmid-19373526>Template:Cite journal</ref><ref>Template:Cite journal</ref> The virus is also associated with the childhood disorders of Alice in Wonderland syndrome<ref name=pmid-28116304>Template:Cite journal</ref> and acute cerebellar ataxia<ref name=pmid-14552515>Template:Cite journal</ref> and, by some evidence, higher risks of developing certain autoimmune diseases,<ref name=pmid-19028369>Template:Cite journal</ref> especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome.<ref name=pmid-21871974>Template:Cite journal</ref><ref name=pmid-22312480>Template:Cite journal</ref> About 200,000 cancer cases globally per year are thought to be attributable to EBV.<ref name=Cancer-Research-UK-200000/><ref name=":0">Template:Cite journal</ref> In 2022, a large study (population of 10 million over 20 years) suggested EBV as the leading cause of multiple sclerosis, with a recent EBV infection causing a Template:Nowrap increase in the risk of developing multiple sclerosis.<ref>Template:Cite journal</ref><ref name=pmid-35025605>Template:Cite journal Related non-technical article: Template:Cite news</ref><ref name=pmid-20369303>Template:Cite journal</ref><ref name=pmid-29892607/><ref>Template:Cite journal</ref>

Infection with EBV occurs by the oral transfer of saliva<ref name=pmid-15546128>Template:Cite journal</ref> 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.<ref name="CDC–2020-09-28-mono">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Infants become susceptible to EBV as soon as maternal 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.<ref>Template:Cite journal</ref> When infection occurs during adolescence or young adulthood, it causes infectious mononucleosis 35 to 50% of the time.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

EBV infects Template:Nobr of the immune system and epithelial cells. Once EBV's initial lytic infection is brought under control, EBV latency persists in the individual's Template:Nobr for the rest of their life.<ref name=pmid-15546128/><ref>Template:Cite journal</ref><ref name=pmid-34239514/>

Virology

File:Viral Tegument.svg

Simplified diagram of the structure of EBV

Structure and genome

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.<ref name=pmid-15546128/> 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 the host cell.<ref name=pmid-21233512>Template:Cite journal</ref> 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."<ref>Template:Cite press release</ref><ref>Template:Cite journal</ref>

Tropism

The term viral tropism refers to which cell types that EBV infects. EBV can infect different cell types, including Template:Nobr and epithelial cells.<ref>Template:Cite journal</ref>

The viral three-part glycoprotein complexes of Template:Nobr 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 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 Template:Nobr 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 the gp42 portion are able to bind to human B cells, but unable to infect.<ref>Template:Cite journal</ref>

Replication cycle

File:EBV infection cycle in healthy humans.png

The EBV replication cycle

Entry to the cell

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).<ref name=Entrez-CR2>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Then, viral glycoprotein gp42 interacts with cellular MHC class II molecules. This triggers fusion of the viral envelope with the cell membrane, allowing EBV to enter the B cell.<ref name=pmid-21233512/> 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.<ref>Template:Cite journal</ref>

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 the viral envelope with the epithelial cell membrane, allowing EBV to enter the epithelial cell.<ref name=pmid-21233512/> Unlike B-cell entry, epithelial-cell entry is actually impeded by viral glycoprotein gp42.<ref name=Entrez-CR2/>

Once EBV enters the cell, the viral capsid dissolves and the viral genome is transported to the cell nucleus.<ref>Template:Cite journal</ref>

Lytic replication

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.<ref name=pmid-21233512/>

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, viral DNA polymerase is responsible for copying the viral genome. This contrasts with latency, in which host-cell DNA polymerase copies the viral genome.<ref name=pmid-21233512/>

Lytic gene products are produced in three consecutive stages: immediate-early, early, and late.<ref name=pmid-21233512/> Immediate-early lytic gene products act as transactivators, enhancing 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).<ref name=pmid-21233512/> Early lytic gene products have many more functions, such as replication, metabolism, and blockade of antigen processing. Early lytic gene products include BNLF2.<ref name=pmid-21233512/> Finally, late lytic gene products tend to be proteins with structural roles, such as VCA, which forms the viral capsid. Other late lytic gene products, such as BCRF1, help EBV evade the immune system.<ref name=pmid-21233512/>

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, the highly stable EBNA-1 gene found across all stages of EBV infection is unaffected.<ref name=pmid-23180656>Template:Cite journal</ref> 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.<ref name=pmid-23180656/> 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 either TPA or sodium butyrate.<ref name=pmid-23180656/>

Latency

File:EBV-cycle-in-immunodeficiency.jpg

Development of Epstein–Barr Virus (EBV)-induced acquired immunodeficiency in patients with genetic susceptibility

Unlike lytic replication, latency does not result in production of virions.<ref name=pmid-21233512/> Instead, the EBV genome circular DNA resides in the cell nucleus as an episome and is copied by host-cell DNA polymerase.<ref name=pmid-21233512/> It persists in the individual's Template:Nobr.<ref name=pmid-15546128/><ref name=pmid-34239514/> Epigenetic changes such as DNA methylation and cellular chromatin constituents, suppress the majority of the viral genes in latently infected cells.<ref name=pmid-32232535>Template:Cite journal</ref> Only a portion of EBV's genes are expressed, which support the latent state of the virus.<ref name=pmid-32232535/><ref name=pmid-15546128/><ref>Template:Cite journal</ref> Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist within Template:Nobr and epithelial cells, but different latency programs are possible in the two types of cell.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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 viral proteins and viral RNAs.<ref name=pmid-17446270>Template:Cite journal The nomenclature used here is that of Kieff. Other laboratories use different nomenclatures.</ref><ref name=pmid-19680535>Template:Cite journal</ref>

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).<ref>Template:Cite journal</ref>

Within B cells, all three latency programs are possible.<ref name=pmid-15546128/> 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.<ref name=pmid-15546128/> Upon infecting 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).<ref name=pmid-15546128/><ref name=pmid-21233512/> 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 a memory B cell.<ref name=pmid-15546128/><ref name=pmid-21233512/> 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.<ref name=pmid-15546128/><ref name=pmid-21233512/>

Within epithelial cells, only Latency II is possible.<ref>Template:Cite journal</ref>

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-cells can result in malignancies, marked by uniform EBV genome presence and gene expression.<ref name=Robertsones>Template:Cite book</ref>

Reactivation

Latent EBV in B cells can be reactivated to switch to lytic replication. This 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.<ref name=pmid-21233512/>

Transformation of B lymphocytes

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.<ref name="pmid31315893"/>

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 is the consequence of viral protein expression.<ref>Template:Cite journal</ref>

EBNA-2, EBNA-3C, and LMP-1, are essential for transformation, whereas EBNA-LP and the EBERs are not.<ref name=Yates1985>Template:Cite journal</ref>

Following a 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 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.<ref name=pmid-19740997/> As a result, the modification by the EBV increases the hosts likelihood of developing EBV related cancer.<ref name=pmid-27933614/> EBV related cancers are unique in that they are frequent in making epigenetic changes but are less likely to mutate.<ref name=pmid-28780440>Template:Cite journal</ref>

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.<ref name=Gratama1988>Template:Cite journal</ref>

Latent antigens

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 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 is alternatively spliced into the transcript.

Protein/genes

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 viral transactivator.
EBNA-3	latent+lytic	These genes also bind the host RBP-Jκ protein.
LMP-1	latent	LMP-1 is a six-span transmembrane protein that is also essential for EBV-mediated growth transformation.
LMP-2	latent	LMP-2A/LMP-2B are transmembrane proteins that act to block tyrosine 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.<ref name=khan>Template:Cite journal</ref> 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.<ref name=pmid-19680535/>
ebv-sisRNA	latent	Ebv-sisRNA-1 is a stable intronic sequence RNA generated during latency program III. After the EBERs, it is the third-most abundant small RNA produced by the virus during this program.<ref name=Moss2013>Template:Cite journal</ref>
miRNAs	latent	EBV microRNAs are encoded by two transcripts, one set in the BART gene and one set near the BHRF1 cluster. The three BHRF1 pri-miRNAS (generating four miRNAs) are expressed during type III latency, whereas the large cluster of BART miRNAs (up to 20 miRNAs) are expressed highly during type II latency and only modestly during type I and II latency.<ref name=Forte2011>Template:Cite journal</ref> 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<ref name=Buisson2009>Template:Cite journal</ref>

Subtypes of EBV

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 the viral genome with a restriction enzyme and comparing the resulting digestion patterns by gel electrophoresis.<ref name=pmid-21233512/>

Detection

Interpretation of specific EBV antibodies

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	+	–	+	+/−

Serological testing is the first-line approach, employing enzyme-linked immunosorbent assays (ELISA) to detect IgM and IgG antibodies against viral capsid antigen (VCA), early antigen (EA) and Epstein–Barr nuclear antigen (EBNA); the pattern of these antibodies differentiates acute, recent, or past infection stages.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Then in situ hybridization using EBER-ISH targets the highly abundant EBV-encoded small RNAs within infected cells, enabling precise localization of latent infection in tissue biopsies and serving as the diagnostic gold standard in pathology.<ref>Template:Cite journal</ref>

Then nucleic acid detection via polymerase chain reaction (PCR) assays allows rapid, sensitive detection of EBV DNA in blood or tissue, although it cannot distinguish latent from active infection and shows poor correlation with clinical symptoms.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Additional methods such as immunofluorescence assays (IFA) offer high specificity and staging capability in specialized laboratories,<ref>Template:Cite journal</ref> and chemiluminescence immunoassays (CLIA) show promise in distinguishing primary from past infections pending further validation.<ref>Template:Cite journal</ref>

Role in disease

See also Infectious mononucleosis and the other diseases listed in this section

EBV causes infectious mononucleosis.<ref>Template:Cite journal</ref> Children infected with EBV have few symptoms or can appear asymptomatic, but when infection 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.<ref name="CDC–2020-09-28-mono"/> Post-infectious chronic fatigue syndrome has also been associated with EBV infection.<ref name=pmid-2855828>Template:Cite journal</ref><ref>Template:Cite journal</ref>

EBV has also been implicated in several other diseases, including Burkitt's lymphoma,<ref>Template:Cite journal</ref> hemophagocytic lymphohistiocytosis,<ref name=pmid-29358936>Template:Cite journal</ref> Hodgkin's lymphoma,<ref>Template:Cite journal</ref> stomach cancer,<ref name=Cancer-Research-UK-200000>Template:Cite press release</ref><ref>Template:Cite journal</ref> nasopharyngeal carcinoma,<ref>Template:Cite journal</ref> multiple sclerosis,<ref name=pmid-35025605/><ref name=pmid-20369303/><ref name=pmid-25740864>Template:Cite journal</ref><ref name=pmid-29892607>Template:Cite journal</ref> and lymphomatoid granulomatosis.<ref>Template:Cite journal</ref>

EBV infected B cells have been shown to reside within the brain lesions of multiple sclerosis patients,<ref name=pmid-29892607/> 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.<ref>Template:Cite news</ref>

Additional diseases that have been linked to EBV include Gianotti–Crosti syndrome, erythema multiforme, acute genital ulcers, and oral hairy leukoplakia.<ref>Template:Cite journal</ref> 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,<ref name=pmid-27900557>Template:Cite journal</ref> Epstein–Barr virus-positive mucocutaneous ulcers, and hydroa vacciniforme as well as malignant lymphoproliferative diseases such as Epstein–Barr virus-positive Burkitt lymphoma,<ref name=pmid-26113842>Template:Cite journal</ref> Epstein–Barr virus-positive Hodgkin lymphoma,<ref name=pmid-28893938>Template:Cite journal</ref> and primary effusion lymphoma.<ref name=pmid-28399009>Template:Cite journal</ref>

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).<ref>Template:Cite journal</ref>

It has been found that EBNA1 may induce chromosomal breakage in 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.<ref>Template:Cite journal</ref> 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 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 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.<ref name="Pyoria2024">Template:Cite journal</ref>

History

The Epstein–Barr virus was named after M.A. Epstein and Yvonne Barr, who discovered the virus together with Bert Achong.<ref>Template:Cite news</ref><ref name=pmid-14107961>Template:Cite journal</ref> 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, 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.<ref name=pmid-14107961/><ref name=Epstein-2005/> Cell lines were sent to Werner and Gertrude Henle at the Children's Hospital of Philadelphia who developed serological markers.<ref name=pmid-6261650/> 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.<ref name=Epstein-2005>Template:Cite book</ref><ref>Template:Cite book</ref><ref>Template:Cite journal</ref> In 1968, they discovered that EBV can directly immortalize B cells after infection,<ref name="pmid31315893">Template:Cite journal</ref> mimicking some forms of EBV-related infections,<ref name=pmid-6261650>Template:Cite journal</ref> and confirmed the link between the virus and infectious mononucleosis.<ref>Template:Cite book</ref>

Research

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.<ref name=pmid-18938248>Template:Cite journal</ref> 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 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.<ref name=pmid-22901543>Template:Cite journal</ref>

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.<ref name=Cancer-Research-UK-200000/><ref name=":0" /> The absence of effective animal models is an obstacle to the development of prophylactic and therapeutic vaccines against EBV.<ref name=pmid-34239514>Template:Cite journal</ref>

It is possible, in theory, that a prolonged use of valaciclovir, an antiviral drug approved to treat herpes simplex or herpes zoster, might lead to Epstein–Barr eradication, but such theory was not confirmed by any study.<ref name=pmid-19740997>Template:Cite journal</ref> 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.<ref name=pmid-27933614>Template:Cite journal</ref>

See also

• Epstein–Barr virus infection
• Epstein–Barr virus-associated lymphoproliferative diseases
• James Corson Niederman, the physician who proved how the Epstein–Barr virus is transmitted in infectious mononucleosis

Further reading

• Template:Cite magazine

External links

• {{#invoke:citation/CS1|citation

|CitationClass=web }}