CANCER PREVENTION INSTITUTE OF CANADA

Last updated: 15-Jan-2007

Epstein Barr Virus

About 100 herpesviruses have been isolated, but it seems that only 8 infect humans. The best known of these are the herpes simplex viruses, types 1 and 2. The herpesviruses are widely separated in genetic make-up, but share a similar complex structure.

EBV infects more than 90% of adults in the world; two subtypes are found in humans, with EBV-1 being the most prevalent. Once infected, an individual is a lifelong carrier.[1],[2],[3] The means of transmission is salivary contact; this is because EBV primarily infects the squamous epithelium and the lymphoid organs (specifically, the B cells) of the oropharynx. Virus can continue to be shed into the saliva for years after primary infection.[4] Most EBV carriers are asymptomatic, though infection in adolescence frequently results in infectious mononucleosis (so-called “kissing disease”). The mechanisms which trigger a small proportion to develop a malignancy remain unclear, though, driven by the hope of discovering therapeutic strategies, they remain an intense focus of theory and research.[5],[6]

EBV was the first human tumour virus identified. It was isolated in 1964 from a common lymphoma in African children first described by Burkitt (after whom the cancer is named). Since that time, EBV has been implicated in a wide variety of cancers, most of which can emerge years after the primary infection.[7] However, the very functioning of EBV, which involves “strategies to minimize or eliminate its pathogenic potential, in the interest of maintaining infection and the survival of the host,” means that causal connections between the virus and disease are difficult to prove.[8] After more than 40 years of research, the picture regarding EBV and oncogenesis remains complex.[9] An inventory of likely EBV-influenced cancers is offered in the next section.

Associated Cancers

As noted, the list of cancers linked to EBV seems to be ever expanding. As Hsu and Glaser noted: “Given that the complexity and duration of EBV-host interaction provides numerous possibilities for a malignant outcome, the heterogeneity of the cancers associated with EBV is not surprising.”[10]

We begin with where the EBV story started, the disease identified by Burkitt. So-called nonendemic Burkitt’s lymphoma is the version of the disorder seen most often in western countries. It has been a rare disorder, though incidence has increased recently because of its association with the immunosuppression due to AIDS. Compared to the endemic version of Burkitt’s lymphoma found in Africa, the nonendemic, AIDS-related form is not as closely associated with EBV; only 15-30% of cases demonstrate the presence of the virus.[11],[12]

EBV is involved with Hodgkin’s disease, though positivity for the virus varies with the subtype of Hodgkin’s (from 10% to more than 95% infection rate). About half the Hodgkin’s cases in the US demonstrate the presence of EBV. However, this rate goes up to 95% in HIV- associated cases.[13] Although not considered an AIDS-defining condition, in developed areas of the world Hodgkin’s lymphoma competes with Kaposi sarcoma as the cancer most diagnosed alongside HIV infection.[14]

Undifferentiated nasopharyngeal carcinoma is strongly associated with EBV.[15],[16] Although mostly rare in the west (the exception being the Inuit), it is common in Canton, Hong Kong, and Taiwan.[17],[18] The latter geographic connection may have something to do with the consumption of salted fish.[19] However, as incidence is high in people of Chinese descent regardless of where they live, immigration may make this disease more of a concern for western countries in the future.[20]

There are several AIDS-related lymphomas which have been linked to EBV.[21] Other routes of becoming immunocompromised (e.g., inherited disorders, transplantation drugs) also can lead to the lymphoproliferative conditions. The AIDS-related versions are either systemic (e.g., Burkitt’s) or target the central nervous system; they tend to be aggressive. The systemic lymphomas demonstrate EBV positivity in 30 to 90% of cases. Finally, there are effusion lymphomas of the visceral cavity that sometimes demonstrate the presence of EBV; these conditions are also associated with human herpesvirus-8 (see below).

Although mainly infecting immune system B cells, EBV also can infect other cells.[22] For example, certain T cell non-Hodgkin’s lymphomas have been associated with the virus. One type, localized in the nasal area, demonstrates a remarkable 90% EBV-positivity.

In addition to the preceding conditions, EBV is also being investigated in the context of breast cancer, certain gastric cancers, salivary gland tumours, hepatocellular carcinomas, and smooth muscle tumours known as leiomyosarcomas (the latter only occurring in immunosuppressed patients).[23],[24],[25],[26],[27] Whatever the theoretical interest in these investigations, it must be admitted that at present any indication of EBV-association does not have prognostic or therapeutic implications.[28]

Preventive Interventions

With such a massive prevalance of EBV infection and its routine oral transmission, it is difficult to hold out much hope for early primary prevention, that is, eliminating exposure to and contration of the infection. As well, given the limited understanding of oncogenetic triggers and mechanisms in the many types of cancer influenced by EBV, effective primary prevention also remains elusive. Recalling the role that immunosuppression plays in the development of certain EBV-associated malignancies (see above), some of the most promising research involves therapies designed to reestablish immunocompetence.[29],[30] This approach can theoretically be used prophylactically or to eradicate existing disease. One research focus has been infusion with cytotoxic T lymphocytes from donors, though this treatment carries its own danger of graft-versus-host disease.[31],[32],[33] Clearly, another approach which can be useful in reducing the incidence of this class of tumours is prevention of HIV infection either through changes in sexual behaviour or by vaccination.[34]

Efforts are also underway to create an EBV vaccine to prevent initial infection or boost immunity in the face of EBV-associated tumours.[35],[36],[37],[38] There are now two candidate vaccines ready for trial.[39] Rounding out the discussion in terms of secondary prevention, broad-spectrum antiherpesvirus agents already in use clinically may have an effect on EBV diseases, though to date “reports of tumour regression remain anecdotal.”[40],[41] Novel EBV-focused treatments are also under investigation. As one study noted, “the consistent presence of…EBV in particular tumor types offers the potential for the development of highly specific, viral-targeted therapies.”[42]

Summing up the progress to date, it must be acknowledged that, whatever the promise of immunotherapies and antivirals, the prevention and management of EBV-related morbidity remains in the “nascent stages.”[43]

[2] Rickinson AB, Callan MF, Annels NE. T-cell memory: lessons from Epstein-Barr virus infection in man. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences. 2000; 355(1395): 391-400.

[3] Dolcetti R, Guidoboni M, Gloghini A et al. EBV-associated tumors: pathogenetic insights for improved disease monitoring and treatment. Current Cancer Therapy Reviews. 2005; 1: 27-44.

[4] Murray PG, Young LS. The Role of the Epstein-Barr virus in human disease. Frontiers in Bioscience. 2002; 7: d519-40.

[5] Niller HH, Salamon D, Ilg K et al. EBV-associated neoplasms: alternative pathogenetic pathways. Medical Hypotheses. 2004; 62(3): 387-91.

[6] Ambinder RF. Epstein-Barr virus-associated lymphoproliferative disorders. Reviews in Clinical & Experimental Hematology. 2003; 7(4): 362-74.

[7] Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clinical Cancer Research. 2004; 10(3): 803-21.

[8] Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. New England Journal of Medicine. 2004; 350(13): 1328-37.

[9] Niedobitek G, Meru N, Delecluse HJ. Epstein-Barr virus infection and human malignancies. International Journal of Experimental Pathology. 2001; 82(3): 149-70.

[10] Hsu JL, Glaser SL. Epstein-barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Critical Reviews of Oncology/Hematology. 2000; 34(1): 27-53.

[11] Dolcetti R, Guidoboni M, Gloghini A et al. EBV-associated tumors: pathogenetic insights for improved disease monitoring and treatment. Current Cancer Therapy Reviews. 2005; 1: 27-44.

[12] Subar M, Neri A, Inghirami G et al. Frequent c-myc oncogene activation and infrequent presence of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood. 1988; 72(2): 667-71.

[13] Gandhi MK, Tellam JT, Khanna R. Epstein-Barr virus-associated Hodgkin's lymphoma. British Journal of Haematology. 2004; 125(3): 267-81.

[14] Dolcetti R, Boiocchi M, Gloghini A et al. Pathogenetic and histogenetic features of HIV-associated Hodgkin's disease. European Journal of Cancer. 2001; 37(10): 1276-87.

[15] Niedobitek G, Agathanggelou A, Nicholls JM. Epstein-Barr virus infection and the pathogenesis of nasopharyngeal carcinoma: viral gene expression, tumour cell phenotype, and the role of the lymphoid stroma. Seminars in Cancer Biology. 1996; 7(4): 165-74.

[16] Dolcetti R, Menezes J. Epstein-Barr virus and undifferentiated nasopharyngeal carcinoma: new immunobiological and molecular insights on a long-standing etiopathogenic association. Advanced Cancer Research. 2003; 87: 127-57.

[17] Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clinical Cancer Research. 2004; 10(3): 803-21.

[18] Busson P, Keryer C, Ooka T et al. EBV-associated nasopharyngeal carcinomas: from epidemiology to virus-targeting strategies. Trends in Microbiology. 2004; 12(8): 356-60.

[19] Hsu JL, Glaser SL. Epstein-barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Critical Reviews of Oncology/Hematology. 2000; 34(1): 27-53.

[20] Young LS, Murray PG. Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene. 2003; 22(33): 5108-21.

[21] Cesarman E. Epstein-Barr virus (EBV) and lymphomagenesis. Frontiers in Bioscience. 2002; 7: e58-65.

[22] Jones JF, Shurin S, Abramowsky C et al. T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. New England Journal of Medicine. 1988; 318(12): 733-41.

[23] Wu MS, Shun CT, Wu CC et al. Epstein-Barr virus-associated gastric carcinomas: relation to H. pylori infection and genetic alterations. Gastroenterology. 2000; 118(6): 1031-8.

[24] Wang CP, Chang YL, Ko JY et al. Lymphoepithelial carcinoma versus large cell undifferentiated carcinoma of the major salivary glands. Cancer. 2004; 101(9): 2020-7.

[25] McClain KL, Leach CT, Jenson HB et al. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. New England Journal of Medicine. 1995; 332(1): 12-8.

[26] Macsween KF, Crawford DH. Epstein-Barr virus-recent advances. Lancet Infectious Diseases. 2003; 3(3): 131-40.

[27] Herrmann K, Niedobitek G. Epstein-Barr virus-associated carcinomas: facts and fiction. Journal of Pathology. 2003; 199(2): 140-5.

[28] Herrmann K, Niedobitek G. Epstein-Barr virus-associated carcinomas: facts and fiction. Journal of Pathology. 2003; 199(2): 140-5.

[29] Khanna R, Tellam J, Duraiswamy J et al. Immunotherapeutic strategies for EBV-associated malignancies. Trends in Molecular Medicine. 2001; 7(6): 270-6.

[30] Taylor GS. T cell-based therapies for EBV-associated malignancies. Expert Opinion in Biological Therapy. 2004; 4(1): 11-21.

[31] Comito MA, Sun Q, Lucas KG. Immunotherapy for Epstein-Barr virus-associated tumors. Leukemia & Lymphoma. 2004; 45(10): 1981-7.

[32] Murray PG, Young LS. Epstein-Barr virus infection: basis of malignancy and potential for therapy. Expert Reviews in Molecular Medicine. 2001; 2001: 1-20.

[33] Gottschalk S, Heslop HE, Roon CM. Treatment of Epstein-Barr virus-associated malignancies with specific T cells. Advanced Cancer Research. 2002; 84: 175-201.

[34] Mueller N. Overview: viral agents and cancer. Environmental Health Perspectives. 1995; 103 Suppl 8: 259-61.

[35] Moss DJ, Khanna R, Bharadwaj M. Will a vaccine to nasopharyngeal carcinoma retain orphan status? Developments in Biologicals. 2002; 110: 67-71.

[36] Lopes V, Young LS, Murray PG. Epstein-Barr virus-associated cancers: aetiology and treatment. Herpes. 2003; 10(3): 78-82.

[37] Bharadwaj M, Moss DJ. Epstein-Barr virus vaccine: a cytotoxic T-cell-based approach. Expert Reviews of Vaccines. 2002; 1(4): 467-76.

[38] Taylor GS. T cell-based therapies for EBV-associated malignancies. Expert Opinion in Biological Therapy. 2004; 4(1): 11-21.

[39] Macsween KF, Crawford DH. Epstein-Barr virus-recent advances. Lancet Infectious Diseases. 2003; 3(3): 131-40.

[40] Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clinical Cancer Research. 2004; 10(3): 803-21.

[41] Abdulkarim B, Bourhis J. Antiviral approaches for cancers related to Epstein-Barr virus and human papillomavirus. Lancet Oncology. 2001; 2(10): 622-30.

[42] Israel BF, Kenney SC. Virally targeted therapies for EBV-associated malignancies. Oncogene. 2003; 22(33): 5122-30.

[43] Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clinical Cancer Research. 2004; 10(3): 803-21.