| Epstein–Barr | |
|---|---|
| Two Epstein–Barr virions | |
| Virus classification | |
| Group: | Group I (dsDNA) |
| Family: | Herpesviridae |
| Subfamily: | Gammaherpesvirinae |
| Genus: | Lymphocryptovirus |
| Species: | Human herpesvirus 4 (HHV-4) |
The Epstein–Barr virus (EBV), also called human herpesvirus 4 (HHV-4), is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis. It is also associated with particular forms of cancer, particularly Hodgkin's lymphoma, Burkitt's lymphoma, nasopharyngeal carcinoma, and central nervous system lymphomas associated with HIV.[1] Finally, there is evidence that infection with the virus is associated with a higher risk of certain autoimmune diseases, especially dermatomyositis, systemic lupus erythematosus,[2][3] rheumatoid arthritis,[3] Sjögren's syndrome,[3] and multiple sclerosis.[4]
Most people become infected with EBV and gain adaptive immunity. In the United States, about half of all five-year-olds and 90–95% of adults have evidence of previous infection.[5] Infants become susceptible to EBV as soon as maternal antibody protection disappears. Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. In the United States and in other developed countries, many people are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or teenage years, it causes infectious mononucleosis 35% to 50% of the time.[6]
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Epstein–Barr virus is named after Michael Anthony Epstein, Professor Emeritus at the University of Bristol and Yvonne Barr, who discovered and documented the virus.[7] In 1961, Michael Anthony Epstein, a pathologist and expert electron microscopist, attended a lecture on "The Commonest Children's Cancer in Tropical Africa—A Hitherto Unrecognised Syndrome." This lecture, by Denis Parsons Burkitt, a surgeon practicing in Uganda, was the description of the "endemic variant" (pediatric form) of the disease that 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, Bert Achong, and Barr. Cell lines were sent to Werner and Gertrude Henle at the Children's Hospital of Philadelphia who developed serological markers. In 1967, a technician in their laboratory developed mononucleosis and they were able to compare a stored serum sample, showing that antibodies to the virus developed.[8][9][10]
The virus can execute many distinct programs of gene expression which can be broadly categorized as being lytic cycle or latent cycle.
From studies of EBV gene expression in cultured Burkitt's lymphoma cell lines, at least three programs exist:
It is also postulated that a program exists in which all viral protein expression is shut off(latency 0).
Epstein–Barr virus and its sister virus KSHV can be maintained and manipulated in the laboratory in continual latency. While many viruses are assumed to have this property during infection of their natural host, they do not have an easily managed system for studying this part of the viral lifecycle. Further, Walter Henle and Gertrude Henle[1], together with Harald zur Hausen, discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related neoplasia[2].
On infecting the B-lymphocyte by binding to the complement receptor, the linear genome circularizes and the virus subsequently persists within the cell as an episome.
In primary infection, EBV replicates in oro-pharyngeal 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.[14]
When EBV infects B-lymphocytes 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.
EBNA-2, EBNA-3C and LMP-1 are essential for transformation while EBNA-LP and the EBERs are not. The EBNA-1 protein is essential for maintenance of the virus genome.[15]
It is postulated that following natural infection with EBV, the virus executes 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 amounts of virus 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, only occasionally reactivating to produce fresh virions. A balance is eventually struck between occasional viral reactivation and host immune surveillance removing cells that activate viral gene expression.
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.[16]
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.
EBV can infect a number of different cell types, including B cells and epithelial cells, and under certain cases, it may infect T cells, natural killer cells, and smooth muscle cells. Infecting both the B cells and the epithelial cells is part of the viral normal cycle to persist. However, the entry mechanism and the proteins involved in entry for these two cells are different.
To infect B cells, the gp350 viral protein binds to the cellular receptor complement receptor 2 (CR2, also known as CD21),[17] and triggers endocytosis. In addition, gp42 binds to MHC class II molecule. Through these interactions, the fusion machinery, composed of gHgL and gB, is triggered and the viral membrane fuses with the endosomal membrane to release viral genetic materials.
To infect epithelial cells, gp350 also binds to CR2; however, endocytosis is not triggered. Then, gHgL interacts with a gHgL receptor (possibly integrins αvβ6 or αvβ8) and the fusion machinery gHgL and gB is triggered to allow fusion on cell membrane. Fusion with epithelial cells is actually impeded by gp42.
The viral three-part glycoprotein complexes of gHgLgp42 mediate B cell membrane fusion; while the two-part complexes of gHgL mediate epithelial cell membrane fusion. EBV that are made in the B cells have low numbers of the gHgLgp42 complexes as the three-part complexes interact with HLA class II 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 have MHC class II. As a result, EBV made from B cells are more infectious to epithelial cells, and EBV made from epithelial cells are more infectious to B cells.
| 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. EBER-particles also induce the production of IL-10 which enhances growth and inhibits cytotoxic T-cells. |
| 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 miRNAS are expressed during type III latency while the large cluster of BART miRNAs (up to 20 miRNAs) are expressed during type II latency. The functions of these miRNAs are currently unknown. |
| EBV-EA | lytic | early antigen |
| EBV-MA | lytic | membrane antigen |
| EBV-VCA | lytic | viral capsid antigen |
| EBV-AN | lytic | alkaline nuclease[18][19] |
The Epstein–Barr virus surface glycoprotein H (gH) is essential for penetration of B cells but also plays a role in attachment of virus to epithelial cells.[20]
In laboratory and animal trials in 2000, it was shown that both antagonism of RA-mediated growth inhibition and promotion of LCL proliferation were efficiently reversed by the glucocorticoid receptor (GR) antagonist RU486.[21]
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