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The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known human herpesvirus types in the herpes family, and is one of the most common
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
es in humans. EBV is a double-stranded DNA virus. EBV is the first identified oncogenic virus, a virus that can cause
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. EBV establishes permanent infection in human B cells. It uncommonly causes
infectious mononucleosis Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adu ...
and is also tightly linked to many
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
diseases (cancers and autoimmune diseases). Various
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifi ...
formulations have been tested in animals and humans; however, none of them were able to prevent EBV infection, thus, no vaccine has been approved to date. Infectious mononucleosis ("mono" or "glandular fever"), is characterized by extreme fatigue, fever, sore throat, and swollen lymph nodes. EBV is also associated with various non-malignant, premalignant, and malignant EBV-associated lymphoproliferative diseases such as
Burkitt lymphoma Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa ...
, hemophagocytic lymphohistiocytosis, and
Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named a ...
; non-lymphoid malignancies such as
gastric cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
and nasopharyngeal carcinoma; and conditions associated with
human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of th ...
such as hairy leukoplakia and
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
s. The virus 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 disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s, especially
dermatomyositis Dermatomyositis (DM) is a Chronic condition, long-term inflammatory disorder, inflammatory Autoimmune disease, autoimmune disorder which affects the skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over ...
,
systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
, and Sjögren's syndrome. About 200,000 cancer cases globally per year are thought to be attributable to EBV. In 2022, a large study following 10 million active US military over 20 years suggested EBV as the leading cause of multiple sclerosis (MS), with a recent EBV infection causing a increase in MS risk development. Related non-technical article: Infection with EBV occurs by the oral transfer of
saliva Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...
and genital secretions. Most people become infected with EBV and gain
adaptive immunity The adaptive immune system (AIS), also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The ac ...
. 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. Most children who become infected with EBV display no symptoms or 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 of the immune system and epithelial cells. Once EBV's initial
lytic The lytic cycle ( ) is one of the two cycles of viral reproduction (referring to bacterial viruses or bacteriophages), the other being the lysogenic cycle. The lytic cycle results in the destruction of the infected cell and its membrane. Bact ...
infection is brought under control, EBV latency persists in the individual's for the rest of their life.


Virology


Structure and genome

The
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
is about 122–180 nm in diameter and is composed of a double helix of
deoxyribonucleic acid Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of a ...
(DNA) which contains about 172,000
base pairs A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
encoding 85
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s. The DNA is surrounded by a protein
nucleocapsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...
, which is surrounded by a tegument made of protein, which in turn is surrounded by an
envelope An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter (message), letter or Greeting card, card. Traditional envelopes are made from sheets of paper cut to one o ...
containing both
lipids Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...
and surface projections of
glycoproteins Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
, which are essential to infection of 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 ncludesthe icosahedral capsid, the capsid-associated tegument complex (CATC) and the dodecameric portal—the viral genome translocation apparatus."


Tropism

The term
viral tropism Tissue tropism is the range of cells and tissues of a host (biology), host that support growth of a particular pathogen, such as a virus (biology), virus, bacteria, bacterium or parasite. Some bacteria and viruses have a broad tissue tropism and ...
refers to which cell types that EBV infects. EBV can infect different cell types, including and epithelial cells. The viral three-part glycoprotein complexes of 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 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.


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 Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
gp350 binds to cellular receptor CD21 (also known as CR2). Then, viral glycoprotein gp42 interacts with cellular
MHC class II MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, macrophages, some endothelial cells, thymic epithelial cells, and B cell ...
molecules. This triggers fusion of 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 Integrins are transmembrane receptors that help cell–cell and cell– extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
. 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. 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 cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
.


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 Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell (biology), cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Desp ...
. 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 A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
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 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 the viral
capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or m ...
. Other late lytic gene products, such as BCRF1, help EBV evade the immune system. EGCG, a
polyphenol Polyphenols () are a large family of naturally occurring phenols. They are abundant in plants and structurally diverse. Polyphenols include phenolic acids, flavonoids, tannic acid, and ellagitannin, some of which have been used historically as ...
in
green tea Green tea is a type of tea made from the leaves and buds of the '' Camellia sinensis'' that have not undergone the withering and oxidation process that creates oolong teas and black teas. Green tea originated in China in the late 1st millenn ...
, 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. 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 is being studied to determine just how to induce immune destruction of latently infected B cells by use of either TPA or sodium butyrate.


Latency

Unlike lytic replication, latency does not result in production of virions. Instead, the EBV genome circular DNA resides in the
cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
as an episome and is copied by host-cell
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
. It persists in the individual's . Epigenetic changes such as DNA
methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
and cellular
chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
constituents, suppress 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 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 the production of a limited, distinct set of viral
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, re ...
and viral RNAs. The nomenclature used here is that of Kieff. Other laboratories use different nomenclatures. 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 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 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 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.


Reactivation

Latent EBV in B cells can be reactivated to switch to lytic replication. This is known to happen ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'', 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.


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. When EBV infects B cells ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'', 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. EBNA-2, EBNA-3C, and LMP-1, are essential for transformation, whereas EBNA-LP and the EBERs are not. 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. 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 in making epigenetic changes but are less likely to mutate. The site of persistence of EBV may be
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
. 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.


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 A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
(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 Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...
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


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 Africa is the world's second-largest and second-most populous continent after Asia. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 20% of Earth's land area and 6% of its total surfac ...
. One can distinguish EBV type 1 from EBV type 2 by cutting the viral genome with a
restriction enzyme A restriction enzyme, restriction endonuclease, REase, ENase or'' restrictase '' is an enzyme that cleaves DNA into fragments at or near specific recognition sites within molecules known as restriction sites. Restriction enzymes are one class o ...
and comparing the resulting digestion patterns by
gel electrophoresis Gel electrophoresis is an electrophoresis method for separation and analysis of biomacromolecules (DNA, RNA, proteins, etc.) and their fragments, based on their size and charge through a gel. It is used in clinical chemistry to separate ...
.


Detection

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


Role in disease

:''See also
Infectious mononucleosis Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adu ...
and the other diseases listed in this section'' EBV causes infectious mononucleosis. Children infected with EBV have few symptoms or can appear asymptomatic, but when infection is delayed to adolescence or adulthood, it can cause
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
,
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
, inflamed throat, swollen
lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s in the neck, enlarged spleen, swollen liver, or rash. Post-infectious
chronic fatigue syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...
has also been associated with EBV infection. EBV has also been implicated in several other diseases, including
Burkitt's lymphoma Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa ...
, hemophagocytic lymphohistiocytosis,
Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named a ...
,
stomach cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a numb ...
, nasopharyngeal carcinoma,
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
, and lymphomatoid granulomatosis. EBV infected B cells have been shown to reside within 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 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 Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the brai ...
aggregation (e.g.
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
,
dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior change (individual), behavior, cognition, movement, and dysautonomia, regulation of automatic bodily functions. Unlike some other dementias, mem ...
, and
multiple system atrophy Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progr ...
). 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 A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
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 the line of the tainted genome undergo
mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...
. Since genes in this area have been implicated in
leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
and is home to a
tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
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.


History

The Epstein–Barr virus was named after M.A. Epstein and
Yvonne Barr Yvonne Margaret Balding (; 11 March 1932 – 13 February 2016) was an Irish virologist when co-discovered the Epstein–Barr virus (EBV), which, because it identified a virus as a cause of cancer in humans, has been called "one of the 20th cent ...
, who discovered the virus together with
Bert Achong Bert Geoffrey Achong (6 December 1928 – 20 November 1996) was a Trinidadian-born pathologist known for co-discovering the Epstein–Barr virus through use of Electron microscope, electron microscopy. Career Achong was born in Trinidad and T ...
. In 1961, Epstein, a
pathologist Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
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 Uganda, officially the Republic of Uganda, is a landlocked country in East Africa. It is bordered to the east by Kenya, to the north by South Sudan, to the west by the Democratic Republic of the Congo, to the south-west by Rwanda, and to the ...
, 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 Middlesex Hospital was a teaching hospital located in the Fitzrovia area of London, England. First opened as the Middlesex Infirmary in 1745 on Windmill Street, it was moved in 1757 to Mortimer Street where it remained until it was finally clos ...
to be cultured. Virus particles were identified in the cultured cells, and the results were published in ''
The Lancet ''The Lancet'' is a weekly peer-reviewed general medical journal, founded in England in 1823. It is one of the world's highest-impact academic journals and also one of the oldest medical journals still in publication. The journal publishes ...
'' in 1964 by Epstein, Achong, and Barr. Cell lines were sent to Werner and Gertrude Henle at the
Children's Hospital of Philadelphia The Children's Hospital of Philadelphia, also known by its acronym CHOP, is a children's hospital in Philadelphia, Pennsylvania. Its primary campus is located in the University City, Philadelphia, University City neighborhood of West Philadelph ...
who developed
serological Serology is the scientific study of serum and other body fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum. Such antibodies are typically formed in response to an infection (against a given mi ...
markers. In 1967, a technician in their laboratory developed mononucleosis and they were able to compare a stored serum sample, showing that
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
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 the link between the virus and infectious mononucleosis.


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 ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' is to use
bacterial artificial chromosome A bacterial artificial chromosome (BAC) is a DNA construct, based on a functional fertility plasmid (or F-plasmid), used for transforming and cloning in bacteria, usually '' E. coli''. F-plasmids play a crucial role because they contain partiti ...
s. 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. 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 is an obstacle to the development of prophylactic and therapeutic vaccines against EBV. It is possible, in theory, that a prolonged use of valaciclovir, an antiviral drug approved to treat
herpes simplex Herpes simplex, often known simply as herpes, is a viral disease, viral infection caused by the herpes simplex virus. Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are Cold sore, ora ...
or herpes zoster, might lead to Epstein–Barr eradication, but such theory was not confirmed by any study. 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 effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...
s.


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


References


Further reading

*


External links

* {{Taxonbar, from=Q24808752, from2=Q6900 Betaherpesvirinae IARC Group 1 carcinogens Infectious causes of cancer Viral diseases