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Epstein-Barr virus: Wikis


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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 possible, but not scientifically proven, cancer causing virus of the herpes family, which includes herpes simplex virus 1 and 2, and is one of the most common viruses in humans. Epstein-Barr virus occurs worldwide. It is known to cause infectious mononucleosis, is implicated in the causation of Burkitt's lymphoma and nasopharyngeal carcinoma[1], and is suspected to have a role in the pathogenesis of chronic fatigue syndrome and multiple sclerosis[2].

Most people become infected with EBV and gain adaptive immunity.[3] 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 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 69% of the time. In immunocompromised individuals, the Epstein-Barr virus can also present as an opportunistic infection known as hairy leukoplakia.



EBV is named after Anthony Epstein and Yvonne Barr, who together with Bert Achong,[4] discovered the virus in 1964 in cells cultured from the tumor specimens sent to them from Mulago Hospital in Kampala, Uganda by Denis Burkitt.[5] 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.[6] Epstein, Barr and Achong were working as a team at the Middlesex Hospital at the time.


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.[7]
  • 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.[8]


From studies of EBV gene expression in cultured Burkitt's lymphoma cell lines, at least three programs exist:

  • EBER1&2 LMP2A EBNA1 (Latency I)
  • EBER1&2 LMP2A LMP2B EBNA1 LMP1 (Latency II)
  • EBER1&2 LMP2A LMP2B EBNA1 LMP1 EBNA2,3,4,5,6 (Latency III)

It is also postulated that a program exists in which all viral protein expression is shut off(latency 0).

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[1], together with Harald zur Hausen who later discovered the papillomaviruses[2] causing cervical cancer, discovered that EBV can directly immortalize B cells after infection, mimicking some forms of EBV-related neoplasia[3].

On infecting the B-lymphocyte by binding to the complement receptor,[9] 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.[10]


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.[11]

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.[12]

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/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 of an unknown role. --> They bind to certain nucleoptrotein particles. Particles that contain EBER bind to PKR (dsRNA dependent serin/threonin protein kinase) and inhibit its function. EBER-particle 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[13][4]

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.[14]

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.[15]

See also


  1. ^
  2. ^
  3. ^ "Mononucleosis". Retrieved 2009-10-27. 
  4. ^ "NIHERST: Caribbean Icons in STI". Retrieved 2008-10-05. 
  5. ^ Epstein MA, Achong BG, Barr YM (March 1964). "Virus particles in cultured lymphoblasts from Burkitt's lymphoma". Lancet 1 (7335): 702–3. doi:10.1016/S0140-6736(64)91524-7. PMID 14107961. 
  6. ^ Coakley D (2006). "Denis Burkitt and his contribution to haematology/oncology". Br J Haematol 135 (1): 17–25. doi:10.1111/j.1365-2141.2006.06267.x. PMID 16939495. 
  7. ^ Lockey TD, Zhan X, Surman S, Sample CE, Hurwitz JL (2008). "Epstein-Barr virus vaccine development: a lytic and latent protein cocktail". Front. Biosci. 13: 5916–27. doi:10.2741/3126. PMID 18508632. 
  8. ^ The nomenclature used here is that of the Kieff lab. Other laboratories use different nomenclatures.
  9. ^ AAP In-Service Exam, 2008-A69
  10. ^ Robertson, ES (editor) (2010). Epstein-Barr Virus: Latency and Transformation. Caister Academic Press. ISBN 978-1-904455-62-2. 
  11. ^ Yates JL, Warren N, Sugden B (1985). "Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells". Nature 313 (6005): 812–5. doi:10.1038/313812a0. PMID 2983224. 
  12. ^ Gratama JW, Oosterveer MA, Zwaan FE, Lepoutre J, Klein G, Ernberg I (1988). "Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency". Proc. Natl. Acad. Sci. U.S.A. 85 (22): 8693–6. doi:10.1073/pnas.85.22.8693. PMID 2847171. 
  13. ^ Buisson M, Géoui T, Flot D, Tarbouriech N, Ressing ME, Wiertz EJ, Burmeister WP (2009). "A bridge crosses the active-site canyon of the Epstein-Barr virus nuclease with DNase and RNase activities". J Mol. Biol. 319 (4): 717–28. doi:10.1073/pnas.85.22.8693. PMID 19538972. 
  14. ^ Molesworth SJ, Lake CM, Borza CM, Turk SM, Hutt-Fletcher LM (July 2000). "Epstein-Barr virus gH is essential for penetration of B cells but also plays a role in attachment of virus to epithelial cells". Journal of virology 74 (14): 6324–32. doi:10.1128/JVI.74.14.6324-6332.2000. PMID 10864642. PMC 112138. 
  15. ^ Quaia M, Zancai P, Cariati R, Rizzo S, Boiocchi M, Dolcetti R (July 2000). "Glucocorticoids promote the proliferation and antagonize the retinoic acid-mediated growth suppression of Epstein-Barr virus-immortalized B lymphocytes". Blood 96 (2): 711–8. PMID 10887139. 

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