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Epstein-Barr Virus
The Epstein-Barr virus was first discovered using electron microscopy of Burkitt’s lymphoma tissue cells in 1964. By 1968, EBV was established as the etiological cause of infectious mononucleosis (Cohen, 2000). EBV is a member of the herpes family of viruses, and is one of the most prevalent viruses, infecting as many as 95% of United States adults (http://www.cdc.gov/ncidod/diseases/ebv.htm).
The Epstein-Barr viral genome is encased within a nucleocapsid and surrounded by a viral envelope. The genome encodes almost 100 viral proteins and infects both epithelial cells and B lymphocytes (Cohen, 2000).
EBV
Infection.
Epstein-Barr virus is generally spread through oral secretions. Most infected individuals shed EBV into the saliva (Cohen, 2000). Because of this method of contraction, the symptoms associated with infection are called the Kissing Disease.
B cell infection is initiated by the EBV envelope glycoprotein gp 350/220, which binds to the B cell CD21 (Speck et al, 2000). CD21 is found on mature B cells as well as follicular dendritic cells. It functions as the receptor for the complement protein C3d, as well as forming the B cell co-receptor when associated with CD19 and CD81 (Janeway et al, 2001). Additional proteins are required for fusion and internalization, including Epstein-Barr glycoproteins gH, gL, and gp42 (Speck et al, 2000).
The mechanism of epithelial cell infection is still unclear. Yoshiyama has shown a CD21 independent route of entry, while Sixbey has demonstrated that epithelial cells expressing IgA antibody receptor can internalize EBV bound to polymeric IgA (Speck et al, 2000). Additionally, cell-to-cell contact is an efficient mechanism for transfer of EBV between epithelial cells (Speck et al, 2000).
Effects
of EBV Infection.
Infected epithelial cells are induced to actively replicate the virus before lysis of the cell, while B cell infection results in immortalization of the cell (Cohen, 2000). Infected B cells express just 10 of the nearly 100 viral proteins encoded by the EBV genome during the latency stage (http://www.science.org.au/nova/026/026key.htm). By generating less viral proteins, the cell has a lower chance of recognition by cytotoxic T cells because of the decreased level of viral peptide expression in Major Histocompatability Complex (MHC) Class I. B cells are believed to be the location for viral persistence because of their ability to evade the immune system and the latency of the virus (Cohen, 2000).
During the latent phase, the virus generates six nuclear antigen proteins (http://www.science.org.au/nova/026/026key.htm). Epstein-Barr virus nuclear antigen (EBNA) 1 allows the viral genome to be maintained as circular DNA, known as an episome. Additionally, EBNA-1 blocks its own degradation by the host proteasome, which prevents its presentation by MHC I (Cohen, 2000). EBNA-2 is an up-regulator of latent membrane proteins (LMP) 1 and 2, which mimic the activity of CD40 and initiate activation of the transcription factor NF-kappa B, inducing B cell proliferation (Cohen, 2000). Because of the activation of a B cell transcription factor, EBV has been implicated in the formation of lymphomas in many patients.
One protein in particular plays in important role in the ability of EBV to survive within a host. The EBV encoded protein BCRF1 has a nearly 70% similar identity to the human Interleukin (IL) 10 cytokine (Hsu et al, 1990). IL-10 is produced by T cells and macrophages, as well as infected EBV B cells and functions as a suppressor of macrophage function (Janeway et al, 2001). It has been shown experimentally, in mice and human cells, that BCRF1 has a similar function to IL-10 (Hsu et al, 1990). By suppressing the macrophage response to EBV, the host immune system is at a disadvantage to rid the body of the pathogen.
(a) (b)
Figure 1. (a) Crystal structure of Epstein-Barr viral protein BCRF1. (b) Crystral structure of Human protein Interleukin-10.
Clinical
Syndromes.
The syndrome most commonly associated with EBV infection is infectious mononucleosis (Mono). The symptoms associated with Mono are generally undetectable during childhood, but adolescents and adults are more likely to display symptoms which include fever, sore throat, and swollen lymph glands (http://www.cdc.gov/ncidod/diseases/ebv.htm). The symptoms generally last for four to six weeks.
Chronic Epstein-Barr virus infection is defined by the presence of severe symptoms for more than six months, organ disease, or presence of virus antigens or DNA in tissue. Unlike chronic fatigue syndrome where a patient exhibits slightly elevated levels of antibody to EBV, patients with chronic EBV infection display extremely elevated antibody levels (Cohen, 2000).
Burkitt’s lymphoma, a malignant lymphoma of small B cells, and nasopharyngeal carcinoma are two cancers associated with EBV infection. It is likely that the evasive mechanisms of the latent Epstein-Barr virus in B cells, and the role of viral proteins in activating transcription factors, contribute to the susceptibility of EBV infected patients to certain cancers.
Treatment of Epstein-Barr Virus.
Currently there is no treatment for patients with infectious mononucleosis. EBV replication can be inhibited by the drug acyclovir, but the virus cannot be erradicated. Certain actions can be taken to reduce the symptoms associated with infection, such as treatment with corticosteroids to reduce fever (Cohen, 2000).
Many patients develop EBV related syndromes as a result of immunosuppresion. In such cases, immunosuppresive drugs should be reduced in order to allow the patients immune system to fight off the viral infection.
References.
Cohen JI. “Epstein-Barr Virus Infection.” New England Journal of Medicine. 343: 481-92.
Epstein-Barr Virus and Infectious Mononucleosis. <http://www.cdc.gov/ncidod/diseases/ebv.htm> Accessed 23 April 2003.
Hsu D, Malefyt R, Fiorentino D, Dang M, Viera P, deVries J, Spits H, Mosmann T, Moore K. “Expression of Interleukin-10 Activity by Epstein-Barr Virus Protein BCRF1.” Science. 250: 830-2.
Janeway CA, Travers P, Walport M, Shlomchik M. Immunobiology: The Immune System in Health and Disease. 5th Edition. New York: Garland
Publishing.
Kissing the Epstein-Barr Virus Goodbye? <http://www.science.org.au/nova/026/026key.htm.> Accessed 23 April 2003.
Speck P, Hann KM, Longnecker R. “Epstein-Barr virus Entry into Cells.” Virology. 277: 1-5.
This page was created by Elizabeth Spitz
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