The Epstein-Barr virus (EBV) infects 96% of adults, often asymptomatically, yet is linked to various cancers and multiple sclerosis. Discovered in 1964, EBV’s connection to cancer was initially met with skepticism. It influences B cell behavior and immune responses, complicating treatment efforts. Recent studies suggest potential links to chronic fatigue and long COVID, fueling renewed research interest.
Author: Finn Holmes
The Epstein-Barr virus (EBV), one of the most successful viruses from an evolutionary perspective, infects approximately 96% of the adult population and can persist in the host for a lifetime. Transmitted primarily through saliva, usually during infancy, EBV often remains asymptomatic but has been linked to various cancers and multiple sclerosis (MS), a topic that will be elaborated upon in this article.
The story of EBV’s discovery traces back 60 years to 1964 in Middlesex, UK, credited to Dr. Anthony Epstein and Yvonne Barr. The first evidence of its existence was serendipitous; during a lecture by Dr. Denis Burkitt, they encountered images of tumors along the jawlines of African populations. This sparked Epstein’s curiosity, leading him to search for the underlying cause of the lymphoma. After years of experimentation, they successfully cultivated a virus in vitro, identifying EBV as the first virus associated with human cancer. The discovery, however, was met with skepticism within the scientific community. A 1966 study in a Philadelphia lab revealed that nearly everyone tested had antibodies against EBV, a surprising outcome given its proposed connection to cancer. Over subsequent decades, researchers noted associations not only with certain cancers but also with multiple sclerosis and immunological diseases like Sjögren’s Syndrome, and more recently, long COVID. Yet, despite six decades of study, a comprehensive understanding of EBV remains elusive.
EBV belongs to the herpesvirus family and is primarily spread via saliva, often infecting children. In rarer instances, usually among adolescents or adults in resource-rich settings, individuals may experience symptoms like fatigue, fever, and swollen lymph nodes for weeks, a condition commonly known as glandular fever or mono, often dubbed the “kissing disease.” The challenges in studying EBV stem from its narrow viral tropism, extensive genome, and low prevalence in healthy populations, with reports indicating that only 1 in 105 B cells are EBV-positive. Nonetheless, as of 2022, nearly 40,000 papers on EBV have surfaced, and that number continues to rise.
Viruses that can lead to cancer fall into two categories: one group, including EBV, induces cancer through gene expression that drives tumor growth, while the second group, like hepatitis C, establishes an inflammatory environment conducive to cancer development. EBV has been implicated in several malignancies, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorder, NK/T cell lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. The varying cancer types linked to EBV are influenced by ethnicity and environmental factors, such as diet. For instance, in Southeast Asia, the prevalence of nasal passage cancer may correlate with dietary fish consumption, while Burkitt lymphoma is more common in sub-Saharan Africa. Genetics also plays a significant role in cancer susceptibility, sometimes quadrupling the risk, alongside factors such as smoking. Globally, around 1% of cancers are identified as EBV-linked, though estimates suggest the actual figure could be as high as 15%. The complexity of EBV’s association with cancer roots from its nature as a “biological accident”—its primary goal is to ensure its own survival rather than to induce cancer. Its close relationship with the human immune system, where immunosuppression is often linked to EBV-related tumors, further complicates matters.
EBV-related nasopharyngeal carcinoma is believed to alter the host’s genome through its encoded DNA, leading to unregulated tumor growth by downregulating tumor suppressor genes, reducing normal protein transcription, and hindering DNA repair mechanisms. This deterioration diminishes the immune system’s ability to respond to tumor growth. EBV also expresses the EBNA-1 gene (found in all EBV-related diseases), which attracts T-cells that inhibit the growth of neoplastic nasopharyngeal carcinoma cells.
The virus is latently maintained in memory B cells (responsible for antibody production), and how this occurs remains a topic of debate. One theory posits that infected cells traverse germinal centers, where specific genes like EBNA-1 promote EBV’s persistence by inactivating latency genes, allowing them to escape immune detection. Another theory suggests that EBV directly infects B cells and inhibits normal somatic hypermutation—the process that diversifies B cells for antigen recognition. This phenomenon relates to Burkitt lymphoma, characterized by chromosomal translocations that lead to the overexpression of the MYC oncogene, causing DNA breaks. EBNA-1 can prevent apoptosis, contributing not only to viral survival but also to the survival of cancer cells. A 2007 study in Uganda involving 325 children diagnosed with Burkitt lymphoma and a control group of healthy children found that those with higher levels of antibodies against EBV were five times more likely to develop Burkitt lymphoma, underscoring the correlation between EBV presence and the disease’s development.
In addition to its role in cancer, EBV is also a causative agent of multiple sclerosis—an autoimmune condition characterized by the immune system attacking the central nervous system. While its symptoms can be unpredictable, a consistent association with EBV exists, as seen in autoimmune diseases. A study in the U.S. indicated that to develop multiple sclerosis, individuals must test positive for EBV, with prior glandular fever increasing the likelihood of MS.
The intricate relationship between EBV and MS is not fully understood and demands further exploration. One potential link involves cross-reactive autoantibodies in MS that frequently target EBV antigens, alongside correlations between CRYAB-specific antibodies and EBNA-1. Another possibility is that EBV immortalizes autoreactive B cells within germinal centers, evading natural elimination processes. These aberrant B cells could then trigger MS, while EBV-infected B cells may induce inflammation in the central nervous system, indirectly contributing to the disease.
Experts propose that mitigating the initial symptoms of glandular fever through therapeutic vaccination might reduce the risk of MS development. However, justifying a vaccine against EBV is challenging due to its widespread transmission. Additionally, an evolutionary perspective suggests a potential symbiosis, proposing that EBV could support the immune system by enhancing B cell effectiveness. Eliminating the virus could inadvertently lead to more harm than good.
Recent associations between EBV, chronic fatigue, and long COVID, alongside the emergence of mRNA vaccines, have reignited interest in EBV research. Future investigations could yield innovative treatments for EBV-related conditions, offering promising insights and breakthroughs in the medical field, and highlighting the potential for addressing illnesses linked to this pervasive virus.
Cover image by: © jarun011 | Getty Images
Edited by: Finn Holmes; Darius Steen
