The Epstein-Barr virus (EBV) belongs to the family of herpes viruses. EBV was first identified as a human tumor virus in Burkitt’s lymphoma (an aggressive blood cancer of the B-cell series) and has subsequently been associated with other lymphomas, epithelial carcinomas and a subgroup of gastric cancers. In addition to its association with various types of cancer in humans, it is also associated with autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis.
Well-adapted pathogen
More than 95% of the world’s population is infected with EBV – making the virus an extremely successful and well-adapted pathogen. Transmission occurs mainly through saliva, but transmission through other body fluids is also possible. In industrialized countries, about 50% of children are infected, and by adolescence, the seroprevalence (laboratory values proving contact with the virus) is already 90%. The primary infection in children is usually asymptomatic. If the primary infection occurs in adolescence, it can lead to infectious mononucleosis – a severe disease also known as “glandular fever”.
After the primary infection, EBV establishes lifelong persistence in the human body, where the virus resides in memory B-cells in healthy people. There it is asymptomatic and does not cause disease symptoms. Due to the high prevalence in the world population, both intrinsic factors (genetics) and external (environmental) factors must be present for EBV-associated diseases (such as MS) to occur.
Two phases possible
EBV can exist in two different phases in the body – the latent and lytic phases. As a rule, EBV is present in its latent form, with lytic phases, in which the virus is reactivated and replicates, only occurring sporadically. During the latent phase, the virus’s genetic material is located in the cell nucleus and is bound to human DNA using a viral protein called EBNA-1. It expresses only a small part of its genes during this phase. This includes the expression of so-called EBV nuclear antigens (EBNAs) and certain latent membrane proteins (LMPs). Numerous interactions with proteins of the human cell nucleus, which are important for the transcription (reading) of genes, have been demonstrated for the EBNAs. The LMPs, on the other hand, interact with various signal transduction cascades that are important for immunological processes. The virus’s replication in the latent phase depends solely on the normal cell division of the infected cells.
Under certain conditions, the virus can reactivate and enter the lytic cycle. A biologically important trigger for a lytic EBV phase is the activation of the B-cell receptor and the differentiation of B-cells into plasma cells. The virus then replicates its entire viral genome and produces infectious offspring. Lytic replication usually leads to the death of the infected cell and the release of infectious viruses that can infect naive cells in the same host or other individuals. Lytic replication of EBV can indeed be inhibited by approved antiviral therapies such as ganciclovir or aciclovir. Studies in healthy volunteers have also shown that prolonged aciclovir therapy can reduce the number of EBV-infected B-cells, which could suggest that the reservoir of infected cells in a host is replenished through the lytic phases. However, since primarily latently infected cells are detected in EBV-positive tumors, the clinical significance of inhibiting lytic phases is unclear.
The EBV infection has – as already mentioned – been linked to several autoimmune diseases, including systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis and multiple sclerosis. Most recently, a study was conducted on over 10 million military personnel in the USA, which revealed a higher rate of EBV infections in MS patients compared to controls and showed that individuals infected with EBV were 32 times more likely to develop MS (Bjornevik et al., 2022). Furthermore, studies found cross-reactive antibodies against EBV EBNA1 and human glial cell adhesion molecules (GlialCAM) in MS patients. EBNA1-specific T cells cross-reacting with myelin antigens were also detected in MS patients. It was also found that a significant number of brain-infiltrating B-cells and plasma cells in post-mortem MS brain samples had an EBV infection. Post-mortem brains of MS patients also showed CD8 cytotoxic T lymphocytes that recognize latent and lytic EBV proteins and interact with EBV-infected B-cells.
This was a (as far as possible) brief summary of the complex interaction between the EBV virus and the human host and some important connections between latent EBV infection and autoimmunity in MS. Those who are interested in more detail are recommended to read a review article that appeared in CELL in 2022 (Damania et al. et al. Epstein-Barr Virus (EBV): Biology and Clinical Disease. Cell 2022; 185: 3652 – 3670). I think it becomes clear even when reading my brief summary that – despite the undisputed importance of the EBV infection – a sole antiviral therapy is certainly not suitable for successfully treating MS. In addition, it can be assumed that processes are already established in the body of MS patients through the (usually unnoticed) primary infection that go beyond the actual infection event. Which processes in the latent virus phase are important for the development of autoimmunity and would potentially need to be inhibited by medication has not yet been clarified. Accordingly, we will have to wait in this regard – and therefore self-medication (with potentially very side effect-rich drugs) is nonsense.
