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Epstein-Barr virus
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The Epstein-Barr Virus (EBV), also called Human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes Herpes simplex virus), and is one of the most common viruses in humans. Most people become infected with EBV, which is often asymptomatic but infection commonly causes infectious mononucleosis (also known as glandular fever).
Epstein-Barr virus occurs worldwide, and most people become infected with EBV sometime during their lives.
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Encyclopedia
The Epstein-Barr Virus (EBV), also called Human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes Herpes simplex virus), and is one of the most common viruses in humans. Most people become infected with EBV, which is often asymptomatic but infection commonly causes infectious mononucleosis (also known as glandular fever).
Epstein-Barr virus occurs worldwide, and most people become infected with EBV sometime during their lives. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. Infants become susceptible to EBV as soon as maternal antibody protection (present at birth) 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 persons are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 55% of the time.
History
EBV is named after Anthony Epstein and Yvonne Barr, who together with Bert Achong, discovered the virus in 1964 in cells cultured from the tumor specimens sent to them from Mulago Hospital in Kampala, Uganda by Denis Burkitt. Burkitt and Epstein had met three years earlier in London during a talk by Burkitt on his findings regarding children's cancers in tropical Africa. In the talk, Burkitt postulated that there may be an infectious component to what he referred to as "African Lymphoma". After the presentation, the two men met and Burkitt agreed to send Epstein frozen specimens for him to analyze. Epstein, Barr and Achong were working as a team at the Middlesex Hospital at the time.
Virology
The virus can execute many distinct programs of gene expression which can be broadly categorized as being lytic cycle or latent cycle.
- The lytic cycle or productive infection results in staged expression of several viral proteins with the ultimate objective of producing infectious virions. Formally, this phase of infection does not inevitably lead to lysis of the host cell as EBV virions are produced by budding from the infected cell. Lytic proteins include gp350 and gp110.
- The latent cycle (lysogenic) programs are those that do not result in production of virions. A very limited, distinct set of viral proteins are produced during latent cycle infection. These include Epstein-Barr nuclear antigen (EBNA)-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-leader protein (EBNA-LP) and latent membrane proteins (LMP)-1, LMP-2A and LMP-2B and the Epstein-Barr encoded RNAs (EBERs). In addition, EBV codes for at least twenty microRNAs which are expressed in latently infected cells.
Programs
From studies of EBV gene expression in cultured Burkitt's lymphoma cell lines, at least three programs exist:
- EBNA1 only (group I)
- EBNA1 + EBNA2 (group II)
- Latent cycle proteins (group III)
It is also postulated that a program exists in which all viral protein expression is shut off.
Latent cycle
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, together with Harald zur Hausen who later discovered the papillomaviruses causing cervical cancer, discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related neoplasia.
On infecting the B-lymphocyte, the linear virus genome circularizes and the virus subsequently persists within the cell as an episome.
Transformation
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.
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.
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 |
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| 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-J? 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 of an unknown role. | | 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
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Surface receptors
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.
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.
External links
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- Editor: Erle S. Robertson Department of Microbiology and the Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA
- Body that organizes the two-yearly EBV research meeting.
- Burt Achong
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