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Template:Taxobox begin Template:Taxobox begin placement virus Template:Taxobox group i entry Template:Taxobox familia entry Template:Taxobox genus entry Template:Taxobox species entry Template:Taxobox end placement Template:Taxobox end 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 Cytomegalovirus), and is one of the most common viruses in humans. Most people become infected with EBV, which is often asymptomatic but commonly causes infectious mononucleosis. It is named after Michael Epstein and Yvonne Barr, who together with Bert Achong discovered the virus in 1964.

Biology

On infecting the B-lymphocyte, the linear virus genome circularises and the virus subsequently persists within the cell as an episome.

The virus can execute several distinct programmes of virally-encoded gene expression which can be broadly categorised as being lytic cycle or latent cycle. The lytic cycle or productive infection results in staged expression of a host of 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.

The latent cycle programmes 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). From studies of EBV gene expression in cultured Burkitt's lymphoma cell lines, at least three programmes exist: EBNA1 only (group I), EBNA1 + EBNA2 (group II) and all latent cycle proteins (group III). It is also postulated that a programme in which all viral protein expression is shut off exists.

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 programmes 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 programmes reprogramme 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) 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.

EBV 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 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-1 possesses a glycine-alanine repeat that impairs antigen processing and MHC class I-restricted antigen presentation thereby inhibiting the CD4-restricted cytotoxic T-cell response against virus infected cells.

EBNA-1 was initially identified as the target antigen of sera from rheumatoid arthritis patients (rheumatoid arthritis-associated nuclear antigen; RANA).

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.

EBNA-2 is the main viral transactivator, switching transcription from the Wp promoters used during initially after infection to the Cp promoter. Together with EBNA-3C, it also activates the LMP-1 promoter. It is known to bind the host RBP-Jκ protein that is a key player in the Notch pathway. EBNA-2 is essential for EBV-mediated growth transformation.

EBNA-3A/EBNA-3B/EBNA-3C also bind the host RBP-Jκ protein.

EBNA-3C is also a ubiquitin-ligase and has been shown to target cell cycle regulators like pRb

LMP-1 is a six-span transmembrane protein that is also essential for EBV-mediated growth transformation. LMP-1 mediates signalling through the TNF/CD40 pathway.

LMP-2A/LMP-2B are transmembrane proteins that act to block tyrosine kinase signalling. it is believed that they act to inhibit activation of the viral lytic cycle. LMP-2A/LMP-2B are not required for EBV-mediated growth transformation.

EBER-1/EBER-2 are small nuclear RNAs of an unknown role. They are not required for EBV-mediated growth transformation.

Pathology

Infectious mononucleosis

Epstein-Barr can cause infectious mononucleosis, also known as 'glandular fever', 'Mono' and 'Pfeiffer's disease'. Infectious mononucleosis is caused when a person is first exposed to the virus during or after adolesence. It is therefore predominantly found in the developed world, as most children in the developing world are found to be already infected by around 18 months of age. EBV antibody tests turn up almost universally positive in developing nations, but only 70-80% positive in the United States.

EBV-associated malignancies

The strongest evidence linking EBV and cancer formation is found in Burkitt's lymphoma and Nasopharyngeal carcinoma.

Burkitt's lymphoma is a type of Non-Hodgkin's lymphoma and is most common in equatorial Africa and is co-existent with the presence of malaria. Malaria infection causes reduced immune surveillance of EBV immortalised B cells, so allowing their proliferation. This proliferation increases the chance of a mutation to occur. Repeated mutations can lead to the B cells escaping the body's cell-cyle control, so allowing the cells to proliferate unchecked, resulting in the formation of Burkitt's lymphoma. Burkitt's lymphoma commonly affects the jaw bone, forming a huge tumour mass. It responds quickly to chemotherapy treatment, namely cyclophosphamide, but recurrence is common.

Other B cell lymphomas arise in immunocompromised patients such as those with AIDS or who have undergone organ transplantation with associated immunosuppression. Smooth muscle tumors are also associated with the virus in malogent patients.

Nasopharyngeal carcinoma is a cancer found in the upper respiratory tract, most commonly in the nasopharynx, and is linked to the EBV virus. It is found predominantly in Southern China and Africa, due to both genetic and environmental factors. It is much more common in people of Chinese ancestry (genetic), but is also linked to the Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental).

Chronic fatigue syndrome

In the late 1980s and early 1990s, EBV became the favoured explanation for chronic fatigue syndrome. It was noted that people complaining of characteristic exhaustion had EBV, although it was also noted EBV was present in almost everyone, even those not complaining of exhaustion. In a four year study, the Centers for Disease Control and Prevention found no association between CFS and infection by a wide variety of human pathogens, including EBV. The chronic fatigue syndrome is what people usually mean if they say they "have Epstein-Barr".

Other diseases associated with EBV

• Stevens Johnson syndrome
• Hepatitis
• Herpes
• Infectious mononucleosis (glandular fever)
• Alice in Wonderland syndrome
• Non-Hodgkin's lymphoma, including Burkitt's lymphoma and primary cerebral lymphoma
• Hodgkin's disease
• Post-transplant lymphoproliferative disorder
• nasopharyngeal cancer (often found in North Africa, Southern China, and the Arctic, associated with consumption of salted meat ).
• Herpangina
• Multiple Sclerosis
• Hairy leukoplakia

References

1. Epstein,M.A. (1964). "Virus particles in cultured lymphoblasts from Burkitt's lymphoma". Lancet. 283: 702–703. PMID 14107961. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
2. The nomenclature used here is that of the Kieff lab. Other laboratories use different nomenclatures.
3. Yates,J.L. (1985). "Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells". Nature. 313: 812–5. PMID 2983224. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
4. Gratama,J.W. (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: 8693–6. PMID 2847171. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
5. Levitskaya,J. (1988). "Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1". Nature. 375: 685–8. PMID 7540727. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
6. Knight, JS. (2005). "Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase". Molecular and Cellular Biology. 25: 1749–1763. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
7. Knight, JS. (2005). "Epstein-Barr virus latent antigen 3C can mediate the degradation of the retinoblastoma protein through an SCF cellular ubiquitin ligase". Proceedings of the National Academy of Sciences of the USA. 102: 18562–18566. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

External links

• Article in The Scientist 13
• CDC website on EBV
• http://phene.cpmc.columbia.edu/RothamstedMirror/ICTVdB/31310001.htm
• Epstein Barr Virus Editor: Erle S. Robertson Department of Microbiology and the Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA
• International Association for Research on EBV Body that organises the two-yearly EBV research meeting.

• Infectious diseases
• Herpesviruses