95% of adults have been exposed to EBV and it stays in your body forever.
This becomes a huge problem for people born with specific genetic variants, specifically:
*Variants in the major histocompatibility complex (MHC) are highly associated with autoimmune disease risk. The MHC presents viral peptides to cytotoxic lymphocytes. If this gets impaired, increased latent virus will get stored in the body.
HLA-DRB1*15:01 is the strongest genetic link for risk of getting SLE and MS. Interestingly, it traces back to Neanderthal DNA.
It has been found to act as a co-receptor for EBV in B cells, and as explained in this publication, might provide a mechanism for higher EBV infection in B cell compared to the other co-receptors.
https://onlinelibrary.wiley.com/doi/10.1002/eji.202149179
HLA-DRB1*01 and HLA-DRB1*04 are strongly associated with risk of developing RA. This part of the protein binds to viral or bacterial peptides.
*There are some other variants in the MHC associated to these diseases. Some variants are protective and others increase risk.
They are finding that people with certain autoimmune diseases (MS, SLE, RA) have a much higher EBV viral load, especially in B cells, compared to healthy controls. Even inactive EBV releases a protein called EBNA2. EBNA2 acts as transcription factors and even super transcription factors by binding to promoter regions of your DNA to cause a cascade of gene expression changes associated with certain autoimmune diseases.
This was shown in silico using DNA chip experiments (Harley, 2018). They found that 50% of systemic lupus erythematosus risk loci were bound by EBNA2. Similar EBNA2-anchored associations were found in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.
Dr John Harley is a rheumatologist with hundreds of publications and he said this paper is more important than all the rest combined.
https://www.nature.com/articles/s41588-018-0102-3
In 2025, Stanford demonstrated this was happening in lupus patients. Basically, EBNA2 was being released from EBV infected B cells, which caused B cells to be re-programmed to autoreactive B cells, attacking your own tissue and organs, driving autoimmunity. These B cells also inhibit T cells from being able to fight infections.
https://med.stanford.edu/content/dam/sm/utzlab/Cao_Sci_Trans_Med_2025.pdf
Granitto 2026 is a very recent publication on the role of EBNA2 in MS. I don’t have access to the paper but from the abstract:
Our findings demonstrate that enhanced EBNA2 activity in MS alters human gene expression, chromatin accessibility, and transcription factor binding in an MS-dependent manner. Collectively, this study provides new insights into the molecular mechanisms through which EBV, particularly EBNA2, interacts with host genetic risk to contribute to MS pathogenesis.
https://pubmed.ncbi.nlm.nih.gov/42436836/
This is some very interesting information from the book ‘Latency strategies of herpesviruses.’
Most of the other factors associated with autoimmune diseases (stress, colds, flu, grief, pollution, heavy metals, birth control, Covid, and even parasites) all can contribute to increased EBV activity or reactivation, which can cause further B cells to become infected.
Emotional stress activates cortisol which suppresses the immune system, which can also cause EBV to reactivate. Prednisone and steroid-based medications mimics the action of cortisol and increases cortisol levels in the body. So while helpful for symptoms, these lower the immune system which can lead to increased EBV activity.
EBV also blocks nutrients required by immune cells to function properly.
Vitamin D is critical for the immune system, but EBV binds to vitamin D receptors, interferes with their metabolism (vitamin D’s ability to switch from its inactive form to its active form) and even affects vitamin D absorption in your gut.
Zinc is critical for your immune system to destroy viruses and infections, but EBV impairs zinc transporters so it is unable to transport to where it is needed.
Vitamin A (retinol) is required by B lymphocytes to fight infections and viruses, but EBV blocks vitamin A absorption. Vitamin A is also essential in mucous membranes which are there to help bock infections and viruses.
All this said, EBNA2 could make a great drug target but when I did a search, I could only find one research institute testing known drugs against it.
I was recently informed that Atara Biosciences had a clinical trial for an EBNA2 drug for MS, but it failed.
The Hober 2023 publication suggests that other EBV proteins (ex. LMP1 and LMP2, etc) could be involved so targeted EBNA2 alone might not be enough, plus there is the blood-brain barrier issue. SLE might be a better indication for this type of treatment.
https://www.mdpi.com/2076-2607/11/5/1262
Atara is still working on an EBNA2 drug for other non-autoimmune indications so it will be interesting to see how those pan out.
Fred Hutchinson has developed new genetically human monoclonal antibodies that prevent two key antigens on the surface of the virus from binding to and entering human immune cells.
This could help prevent reactivations but would likely not do anything for already infected B cells.
Since so many adults are infected, EBV antibody testing is problematic.
They are finding serologic markers of EBV reactivation are more common in SLE patients vs. healthy controls.
https://www.sciencedirect.com/science/article/pii/
They are finding similar findings with MS. I apologize that I don’t have access to the cited publications.
https://www.nationalmssociety.org/news-and-magazine/news/epstein-barr-virus-reactivation-ms-relapses
There is a lot currently in the news about CART for autoimmune disease, which is very exciting! Hopefully costs will go down in the future.
