How does Epstein-Barr virus cause cancer and lymphoma?

How Epstein-Barr Virus Causes Cancer and Lymphoma

EBV causes cancer and lymphoma primarily by infecting and transforming B lymphocytes through expression of latent viral proteins that drive uncontrolled cell proliferation while evading immune surveillance, with the specific oncogenic mechanism varying by the degree of immune suppression and the viral latency pattern expressed. 1

Primary Mechanism of Oncogenesis

B-Cell Transformation

• EBV primarily infects B lymphocytes using CD21 (complement receptor 2) as its entry receptor, where it establishes latent infection and has the inherent ability to transform and immortalize these cells. 2, 3
• The virus expresses latent proteins including EB nuclear antigens (EBNAs 1,2, 3A, 3B, 3C, and EBNA-leader proteins) and latent membrane proteins (LMPs 1, 2A, and 2B) that drive cellular proliferation. 1
• In nasopharyngeal carcinoma, EBV latent-gene expression is predominantly restricted to EBNA1, LMP2A, and LMP2B—these viral proteins are poorly immunogenic, allowing cancer cells to evade immune recognition. 1

Immune Evasion Strategy

• The International Agency for Research on Cancer classifies EBV as "Group 1" with sufficient evidence of carcinogenicity in humans. 1
• EBV-infected cells persist by expressing minimal latency genes, thereby avoiding destruction by EBV-specific cytotoxic T-lymphocytes, which are normally the most important immune mechanism for controlling infected cell proliferation. 1, 2
• When T-cell immunosurveillance is impaired (such as in transplant recipients or patients on immunosuppressive therapy), enhanced EBV latent gene expression drives proliferation of EBV-infected B-cells with attendant risk of lymphoproliferative disorders and lymphoma. 1

Disease-Specific Mechanisms

Post-Transplant Lymphoproliferative Disorders (PTLD)

• PTLD arises predominantly from EBV-infected B lymphocytes in immunosuppressed patients, with primary EBV infection in the first post-transplant year associated with much higher risk. 1, 2
• The oncogenic potential relates specifically to EBV's ability to transform and immortalize B lymphocytes, leading to uncontrolled proliferation when immune surveillance is compromised. 2

Thiopurine-Associated Lymphomas

• In inflammatory bowel disease patients on thiopurines, current therapy carries a hazard ratio of 5.28 for lymphoproliferative disorder development, with 12 of 15 lymphomas being PTLD-like and usually EBV-associated. 1
• Primary EBV infection poses particular threat: among patients under 50 years on thiopurines, fatal infectious mononucleosis-associated lymphoproliferative disorders have been documented. 1

Nasopharyngeal Carcinoma

• EBV is almost always a necessary, even if not sufficiently causative, factor for non-keratinising nasopharyngeal carcinoma. 1
• Latent EBV has been found in high-grade dysplasia and cancer cells but not in normal epithelium or low-grade dysplasia, and has been identified in a clonal pattern in pre-invasive lesions containing EBV RNAs characteristic of latent infection. 1

Alternative Target Cells in Specific Conditions

T-Cell and NK-Cell Lymphomas

• In chronic active EBV infection (CAEBV), the virus distinctly targets cells other than B lymphocytes, including T cells and NK cells, with patients often developing T-cell or NK-cell lymphoproliferative disorders and malignant lymphomas during disease progression. 1, 2, 4
• Trans-synaptic acquisition of the EBV receptor CD21 from EBV-infected B cells may be responsible for this unusual mode of infection in NK cells. 1
• Cells infected with EBV in CAEBV patients are often not positive for CD8, suggesting deficiency of cytotoxicity as a causative factor in the immunological disturbance. 1

Latency Patterns and Oncogenic Potential

Variable Latency Programs

• EBV-associated B-cell lymphomas express different latency patterns (latency I, II, or III) depending on the specific disease entity, with latency I being most restrictive (expressing only EBNA1 and EBERs) and latency III expressing the full panel of latent viral genes. 2, 5
• Latency I tumors such as Burkitt lymphoma evade the host immune response to EBV and are resistant to EBV-specific T-cell therapies because they express minimal viral antigens. 5
• Latency II and III programs express LMP1/2 and EBNA 2,3, and LP which induce robust T-cell responses, making these tumors more susceptible to immune-based therapies. 5

Critical Clinical Pitfalls

• Assuming EBV is merely a passenger virus rather than a driver of oncogenesis can lead to missed opportunities for EBV-directed therapies. 3, 6
• The magnitude of EBV antibody response and increased viral load in tissues suggest both unusual EBV replication and aberrant cell proliferation of EBV-infected cells as major factors in disease development. 1
• Discontinuation of immunosuppressive therapy may result in spontaneous regression of EBV-associated lymphoproliferative disease, highlighting the critical role of immune surveillance. 1
• In CAEBV, some patients develop oligoclonal or monoclonal lymphoproliferation that eventually results in T-cell or NK-cell malignant lymphomas, making early recognition critical. 4, 7