Epstein–Barr virus

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"EBV" redirects here. For other uses, see EBV (disambiguation).

Human gammaherpesvirus 4
Electron microscopic image of two Epstein-Barr virus virions (viral particles) showing round capsids (protein-encased genetic material) loosely surrounded by the membrane envelope
Electron micrograph of two Epstein–Barr virions (viral particles) showing round capsids loosely surrounded by the membrane envelope
Virus classification Edit this classification
(unranked): Virus
Realm: Duplodnaviria
Kingdom:
Heunggongvirae
Phylum: Peploviricota
Class: Herviviricetes
Order: Herpesvirales
Family:
Orthoherpesviridae
Genus: Lymphocryptovirus
Species:
Human gammaherpesvirus 4
Synonyms[1]
  • Epstein-Barr virus
  • Human herpesvirus 4
  • HHV-4
  • EBV

The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus.[2] Epstein–Barr virus (EBV) is the first identified

mononucleosis and is also tightly linked to many malignant diseases. 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.[3]

The virus causes

Sjögren'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 of multiple sclerosis, with a recent EBV infection causing a 32-fold increase in the risk of developing multiple sclerosis.[14][15][16][17][18]

Infection with EBV occurs by the oral transfer of saliva[19] 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.[20] 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.[21] When infection occurs during adolescence or young adulthood, it causes infectious mononucleosis 35 to 50% of the time.[22]

EBV infects

lytic infection is brought under control, EBV latency persists in the individual's memory B cells for the rest of their life.[19][23][24]

Virology

Simplified diagram of the structure of EBV

Structure and genome

The

glycoproteins, which are essential to infection 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]

Tropism

The term

epithelial cells.[28]

The viral three-part glycoprotein complexes of

class II molecules present in B cells in the endoplasmic reticulum and are degraded. In contrast, EBV from epithelial cells are rich in the three-part complexes because these cells do not normally contain HLA class II molecules. As 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.[29]

Replication cycle

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

CD21 (also known as CR2).[30] 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.[25] 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.[31]

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.[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 the cell nucleus.[citation needed]

Lytic replication

The

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.[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, viral DNA 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 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).[25]
Early lytic gene products have many more functions, such as replication, metabolism, and blockade of antigen processing. Early lytic gene products include BNLF2.[25] 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.[25]

PI3-K pathway through BRLF1, the latter completely abrogating the ability of a BRLF1 adenovirus vector to induce the lytic form of EBV infection.[32] 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.[32]

Latency

Unlike lytic replication, latency does not result in production of virions.[25] Instead, the EBV genome circular DNA resides in the cell nucleus as an episome and is copied by cellular DNA polymerase.[25] It persists in the individual's memory B cells.[19][24] Epigenetic changes such as DNA methylation and cellular chromatin constituents, suppress the majority of the viral genes in latently infected cells.[33] Only a portion of EBV's genes are expressed, which support the latent state of the virus.[33][19][34] Latent EBV expresses its genes in one of three patterns, known as latency programs. EBV can latently persist within

epithelial cells, but different latency programs are possible in the two types of cell.[citation needed
]

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

RNAs.[35][36]

Gene Expressed
EBNA-1
EBNA-2
EBNA-3
A
EBNA-3
B
EBNA-3
C		 EBNA-LP LMP1
LMP-2
A
LMP-2
B
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).[37]

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 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).[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 a memory 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.[38]

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.[39]

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.[25]

Transformation of B lymphocytes

When EBV infects B cells

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.[40]

EBNA-2, EBNA-3C, and LMP-1, are essential for transformation, whereas EBNA-LP and the EBERs are not.[41]

Following natural infection with EBV, the virus is thought to execute some or all of its repertoire of gene expression programs to establish a persistent infection. Given the initial absence of host

immunity
, the lytic cycle produces large numbers of virions to infect other (presumably) B-lymphocytes within 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.[42] As a result, the modification by the EBV increases the hosts likelihood of developing EBV related cancer.[43] EBV related cancers are unique in that they are frequent to making epigenetic changes but are less likely to mutate.[44]

The site of persistence of EBV may be

transplantation.[45]

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.[46] 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.[36]
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.[47]
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.[48] 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[49]

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.[25]

Detection

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.[46]

Role in disease

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

EBV causes infectious mononucleosis.

chronic fatigue syndrome has also been associated with EBV infection.[51][52]

EBV has also been implicated in several other diseases, including

Hodgkin's lymphoma,[55] stomach cancer,[12][56] nasopharyngeal carcinoma,[57] multiple sclerosis,[15][16][58][17] and lymphomatoid granulomatosis.[59]

Specifically, EBV infected B cells have been shown to reside within the brain lesions of multiple 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.[60]

Additional diseases that have been linked to EBV include

Epstein–Barr virus-positive Hodgkin lymphoma,[64] and primary effusion lymphoma.[65]

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).[66]

It has been found that

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.

History

The Epstein–Barr virus was named after

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.[69][70] Cell lines were sent to Werner and Gertrude Henle at the Children's Hospital of Philadelphia who developed serological markers.[71] 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.[70][72][73] In 1968, they discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related infections,[71] and confirmed the link between the virus and infectious mononucleosis.[74]

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.[75] 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.[76]

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.[12][13] The absence of effective animal models is an obstacle to development of prophylactic and therapeutic vaccines against EBV.[24]

Like other

human herpesviruses Epstein-Barr might allow its own eradication via a course of the drug valaciclovir, but further research is needed to determine if eradication is actually achievable.[42] 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.[43]

See also

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Further reading

External links

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