Epstein-Barr Virus and Hodgkin Lymphoma
Hodgkin lymphoma (HL) is a neoplasm that arises from germinal center or post-germinal center B cells. HL has a unique cellular composition, containing a minority of neoplastic cells in an inflammatory background. It is separated from the other B cell lymphomas based on its unique clinicopathologic features. HL accounts for approximately 10 percent of all lymphomas and approximately 0.6 percent of all cancers diagnosed, annually, in the developed world. This represents approximately 9,050 new cases and about 1,150 deaths in the United States, annually. The incidence in Europe is approximately 2.4 cases per 100,000 persons.
Data Linking Epstein-Barr Virus and Hodgkin Lymphoma
There is a strong association between HL and Epstein-Barr virus (EBV). EBV is a ubiquitous herpesvirus that is transmitted mainly via saliva between susceptible persons and asymptomatic EBV shedders. The majority of patients with EBV infections are subclinical. Antibodies to EBV have been demonstrated in all population groups with a worldwide distribution; approximately 90 to 95 percent of adults are EBV-seropositive.
Early epidemiologic data suggested that HL develops among persons with a delayed exposure to EBV. These and subsequent studies proposed EBV as the most likely inducing agent in a significant fraction of cases. EBV infection is associated with an increased risk of EBV-positive, but not EBV-negative HL. The rate of EBV positivity among HL tumors varies by geography, patient ethnicity, histologic subtype, and age. Nucleic acids and proteins from EBV are detected in the malignant cells of 20 to 50 percent of cases of classical HL in North America and Europe. Patients with HL have a distinctive serologic profile of antibodies to EBV antigens. In one report, increased risk of HL was associated with elevated anti-EBV viral capsid antigen (VCA) IgG antibody titers, or an anti-EBNA-1/anti-EBNA-2 antibody ratio ≤1.0.
Mechanisms Describing How Epstein-Barr Virus Causes Hodgkin Lymphoma
EBV infected tumor cells express a subset of EBV genes including latent membrane protein 1 (LMP1), LMP2a, and EBV nuclear antigen 1 (EBNA1). EBNA1 expression is required for the replication and maintenance of the viral genome in proliferating cells, but a role in the pathogenesis of HL has not been determined. However, LMP1 and LMP2a appear to play a role in the development of at least a subset of HL cases by helping such tumors escape programmed cell death (apoptosis). LMP1 produces a tonic survival signal, perhaps through the activation of nuclear factor kappa B (NF-kB). LMP2a is an integral membrane protein that contains motifs that resemble those of immunoglobulin molecules. Expression of LMP2a has been shown to prevent apoptosis of pre-B cells that fail to express Ig molecules.
Treatment of Epstein-Barr Virus and Present Treatment Limitations
Acyclovir is an antiviral medication for EBV that inhibits permissive EBV infection through inhibition of EBV DNA polymerase, but it has no effect on latent infection, which means the viral genome remains viable. A meta-analysis of five randomized controlled trials studying acyclovir in the treatment of acute infectious mononucleosis, including two trials of intravenous therapy in patients with severe disease, failed to show a clinical benefit compared with placebo. Anecdotal use of other agents such as interleukin-2, interferon alfa, and intravenous immunoglobulins in EBV-associated diseases are currently being studied. Additionally, adoptive cell therapy with EBV specific cytotoxic T cells is being evaluated in patients with EBV associated lymphoproliferative disorders and EBV associated malignancies. Accordingly, the introduction of cytotoxic T cells specific for EBV could help eradicate infected host cells.
What Type of Epstein-Barr Virus Treatment is Needed?
Overall, development of a treatment solution that could enhance the immune system’s ability to seek out EBV infected host cell could have a significant benefit in reducing the risk of Hodgkin’s Lymphoma.