- Genetics and infection with the Epstein-Barr virus can increase the risk of developing MS.
- A new study has linked these factors, showing that an MS risk gene changes the immune response to EBV.
- Targeting EBV may provide new opportunities to understand, prevent and treat MS.
A recent study published in the Proceedings of the National Academy of Sciences USA has provided new insights into the link between genetic and environmental risk factors for MS. Researchers have found that a key genetic risk factor for MS influences how the immune system responds to the Epstein-Barr virus (EBV), the strongest environmental risk factor for the condition.
Strongest environmental and genetic risk factors for MS
Genetic studies have shown that people with specific variations in their HLA Class II genes, especially a variant called HLA-DR15, are at a much higher risk of developing MS.
Meanwhile, large studies have confirmed that almost everyone who develops MS has been previously infected with EBV, a virus that can lie dormant in the immune system for life but occasionally reactivates.
HLA Class II molecules are critical to how the immune system recognises and responds to invaders. Think of these molecules as “arms” that reach out from the surface of immune cells. Their “hands” hold pieces of bacteria or viruses to show other immune cells what to attack.
This process helps initiate a targeted immune response. The shape of these “hands” is determined by a person’s genetics, influencing which molecules the immune system recognises and how it reacts.
This study reveals that an HLA-DR15 MS risk gene allows these hands to present EBV proteins when the virus is active. This may explain the stronger immune response to EBV observed in people with the MS risk gene.
What was the aim of the study?
The aim of this study was to investigate whether there is a link between a person’s HLA Class II genetics and their immune response to EBV.
Using AI to predict how MS risk genes will “display” EBV
To investigate this, the team first examined the molecular structure of HLA Class II genes known to increase MS risk.
The HLADR15 gene region is of particular significance as carrying two copies of this variant raises a person’s MS risk by eight times.
The team examined the “hands”, known as peptide binding grooves, of the HLA Class II and used artificial intelligence (AI) to screen them against a database of EBV proteins.
The AI predicted that two specific fragments from an EBV protein called glycoprotein B (gB) fit into the “hands” of the HLA Class II molecules associated with MS risk.
This suggests that these risk genes may uniquely enable the immune system to recognise and respond to specific EBV proteins, potentially linking genetic and environmental factors in MS.
Do the MS risk genes alter the immune response to EBV?
Next, the team showed that these EBV gB protein fragments triggered an immune response in cells from people who carry the MS risk HLA Class II genes.
In contrast, no such response was observed in people without these MS risk genes.
The team also identified another EBV protein called gH, that only individuals with the MS risk HLA Class II genes could respond to.
This indicates that people with these genetic risk factors are uniquely capable of generating immune responses to both gB and gH proteins, which are produced by EBV during its active, or “lytic,” phase of infection.
This study also found that people with the MS risk gene use a unique immune system pathway to respond to EBV.
This pathway bypasses some of the normal checks and balances, meaning immune responses to EBV may happen more frequently or intensely in those with the risk gene.
This could help explain why EBV plays a role in MS development.
How does this relate to MS development?
Scientists are working to understand why EBV infection is necessary for the development of MS.
One important clue is that certain proteins in the brain and spinal cord have a structure similar to parts of EBV.
This means that the immune system might mistakenly attack these areas when it is trying to fight EBV, a phenomenon known as “molecular mimicry.”
For people with the MS risk genes, this mistaken immune attack may be more likely, as their immune system shows a heightened response to specific EBV proteins.
This could increase the chance of generating an autoimmune response that damages the brain and spinal cord, ultimately contributing to the development of MS.
What does this mean for people with MS?
This study has revealed that people with the HLA Class II risk genes can uniquely generate an immune response to two EBV proteins produced during the virus’s lytic phase.
The immune response to EBV may play a role not only in the development of MS but also in ongoing diseases processes.
As a result, targeting EBV could become an important focus for treating or even preventing MS. Researchers are actively investigating potential strategies, and you can read more about these approaches here.
Suppressing EBV reactivation with antivirals in MS
One potential strategy for the management of MS is to suppress the reactivation (“lytic phase”) of EBV using antiviral medication.
However, it is currently unknown whether suppressing EBV can effectively reduce MS activity, or how well these medications work.
The research team, based at Harvard Medical School, is conducting a clinical trial of an antiviral medication in people with MS to explore this approach.
They are studying a medication called tenofovir/emtricitabine (Truvada), which is already approved for treating HIV. The trial aims to determine whether tenofovir/emtricitabine can effectively suppress EBV infection and is safe and tolerable in people with MS.
Dr Natalia Drosu and Professor Michael Levy, the lead authors of this study, are also advisors for an Australian collaborative team in the development of Australian clinical trials of antiviral medications to treat EBV in MS, set to commence recruitment in 2025.
MS Australia is a partner organisation in these efforts, and has recently launched a new EBV National Collaborative Research Platform to support Australian research into EBV’s role in MS. Read more on EBV clinical trials and Australian EBV research here.
