#5 – Epstein–Barr Virus: Why Almost Everyone Gets Infected

[Music] Basically once you're infected, you don't get really rid of these virus anymore. As they say, herpes viruses are forever, like diamonds. [Music] Virological with Florian Kramer. [Music] Welcome to this week's episode of Virological. This was recorded on March 8th of 2026 in Helsinki in Finland. Today we're going to talk about the Epstein-Pah virus or EBB. This is nothing to do with Jeffrey Epstein. We'll get to the name a little bit later. We used to joke that we would open a bar for Virologist. That's called the Epstein-Pah. Unfortunately, that's not funny anymore since all these Epstein stories came up. But the virus itself is really important and interesting. It has been implicated as one of the causes of multiple sclerosis very recently. So we're going to discuss this. The virus is a double-stranded DNA virus. Belongs to the Herpes viruses. Herpes viruses are a large group of DNA viruses with a number of members that are medically relevant. We'll talk about more of the members of the Herpes viruses in the future. And these viruses have a relatively large genome in comparison to the viruses we have discussed so far. Epstein-Pah has a genome of about 170,000 base bears, so 170,000 nuclear diets. And just this comparison, that's about 10 times as much as influenza A in terms of genome size. It does code for a lot of proteins, about 80 different proteins. And it's about 120 to 180 nanometers in diameter. So that's actually not that big. You would expect that if it has a huge genome, maybe it's bigger. But it does have a complicated structure. And again, it produces a lot of proteins when it infects ourselves. A lot of different ones. In terms of the structure, on the inside we have the DNA genome, double-stranded DNA genome. That's associated with nuclear capsid protein. And then that's surrounded by the degeneration protein, degeneration protein, which is basically similar to a matrix protein in a way. And then on the outside we have lipid envelope. And in this lipid envelope we have a number of different glycoproteins, number of different spike proteins. So a lot of the viruses that we usually deal with have 102 spike proteins, you know, SARS-CoV-2 has one spike protein. In fact, it says simbacutein and neurominidase, so that's two. But epsimbaravirus has a lot of different glycoproteins. They're called GH, so G for glycoprotein, GH, GL, GB, GM, GN, GP42, GP50, GP220. And that already indicates that it's a complicated virus and it has a complicated life cycle. In fact, these different glycoproteins, these different spike proteins and complexes of these proteins together, may facilitate, or do facilitate infection of different types of cells and binding to different receptors on these different types of cells. And so some of these receptors that the virus binds to are CD21, MHC2, which is a major protein of the immune system, complement receptors, integrins, and so on and so forth. It's really dependent on the cell type, what kind of receptor the virus is using. The interesting part here is also that we have complicated infection cycle with primary infection, and then we also have a persistent infection. Basically, once you're infected, you don't get really rid of these virus anymore, as they say, Herpes viruses are forever, it's like diamonds. So during the primary infection, the virus infects mostly petalial cells, and it replicates in these cells. It goes in, it starts virus production, and more viruses produce, at some point these viruses die, and the virus spreads to other cells. And that's what we call the "lytic cycle", so it lices these cells. But for example, when it infects B cells, so B cells are major immune cells that makes antibody, then it starts the infection, but it doesn't actually produce more virus, it doesn't actually produce a lot of its own proteins, you can stay dormant there, and that's what we call the latent infection. And so it can do that, and basically at some point in time it can wake up and be reactivated, and then this can turn on a lytic cycle, and then viruses produce. But it can stay dormant for a very long time in B cells, and the immune system doesn't really see it there. So how does this work? Basically the virus generates or the virus integrates itself into the nucleus of the cell. So not into our genome, like HIV would do, but it just basically deposits a copy of its genome, circular DNA copy into the nucleus, and that acts like an extra chromosome basically. So that's there in addition to our chromosomes, and that's called an episome, and that's how it stays there. It's not completely silent in a way, it actually changes the B cell biology a little bit, so it immortalizes these B cells, and it also changes their gene expression a little through epigenetic changes. And that's not great because you don't want cells in your body to be immortalized, that means they don't die anymore, that's not good. You want your cells at some point to die, because otherwise they might become cancerous cells, and that can happen here. And the same is true for these epigenetic changes, that means that the expression of the B cell proteins changes, and that can also change cell behavior. That's not a good thing, but the virus also uses that to get distributed all over the body with the circulating B cells. By the way, this infection is actually very, very common, about 90 to 95% of adults are globally infected with Epstein-Pah virus, and most of them don't have symptoms, but they carry the virus and they can actually pass it on. Going back a little bit to history, the name of the virus comes from Sir Michael Anthony Epstein and Iwon Bar, the two of them discovered the virus in 1963. That's actually an interesting story. Michael Anthony Epstein was listening to a scientific presentation by Dennis Barstend-Burkit, a clinician who worked in Uganda, who was interested in lymphomas, Burkit lymphomas, named after him, and Epstein asked Burkit if he could get samples from some of his patients, and so Burkits and samples to England were Epstein and Power worked in 1963, and then they found the virus in these samples, and that's why the virus is called Epstein-Pah virus. What does the virus do in our body? How do we even get infected? Typically you can get infected through respiratory droplets, through smear infections, contact, direct contact with other people, bodily fluids, sexual contact, and the primary disease that is associated with Epstein-Pah virus infections is known as mononucleosis. A lot of people get infected when their kids and then these infections are often asymptomatic. The kids don't even get mono. They often get infected in kindergarten and take care of settings, where there's a lot of interaction, a lot of playing, a lot of touching, potentially also exchange of bodily fluids through saliva and all kinds of other interactions that they might have. If that happens, then typically there are no symptoms and the kids are infected. A proportion of individuals make it without infections through early childhood, and they get infected during adolescence and poverty, and that often leads to symptomatic infections. This often happens with the first sexual contact or kissing, and that's also why this is called kissing disease sometimes. Here the symptoms are often fatigue, fever, swollen lymph nodes, and large spleen. This can also last quite some time and can lead to some chronic fatigue. A colleague of mine had that he was actually older, he was in his early studies, I believe, and he was really without energy and for a very long time. This virus really trains your energy and makes it really hard to be productive. Then large spleen is also interesting, and that can be problematic because if the spleen is enlarged and you have an accident, you follow something like that, the spleen can rupture and that can be highly problematic. And so the symptoms are often caused by a lot of problems. Those are the normal consequences of an abstin-power virus infection. Typically, you make an immune response at some point and the virus goes into hiding because of that, because you know, they're circulating neutralizing antibodies, and so basically it becomes late and then just stays there. But the problem is the virus, because it does what it does, it can immortalize cells, it changes the cell's behavior. It's also associated with different types of cancer, including different types of lymphoma, gastric cancer, nasopharyngeal cutcinoma, and that is of course problematic. And unfortunately, in some cases, the outcomes of these cancer types are not that great. There is also a connection to the mancher and Parkinson's, although that's not 100% here, but it seems that the virus plays a role there as well. And interestingly, it can also be found in tumor cells of breast cancer, but I think the story there is more or less that the cancer occurs first, and then these cells become more susceptible to infection with EBV, and that's where they are positive. So I think the idea there is that it's not EBV that causes the cancer initially. So as I mentioned, 90 to 95% of individuals are infected. I also mentioned that immunity, typically is induced after the primary infection, and so the virus goes latent, goes into hiding. One thing is this latent phase and the hiding of the virus in the nucleus in terms of debositing its genome as an episome in the nucleus. But it's also very good in dealing with diesel responses and basically surviving diesel surveillance. So it's really good in undermining the immune system. Something that was found more recently in the last few years is a strong connection to multiple sclerosis. Multiple sclerosis is a pretty bad autoimmune disease where the immune system attacks, mylene sheets on nerve cells. So basically the immune system slowly destroys nerve cells. This mylene sheets, these are basically protein sheets that cover nerve cells on the outside, kind of the insulation of neurons, electric insulation of neurons, and you can imagine if that sheet, if that surface gets destroyed, they might not work well anymore. And so multiple sclerosis has different disease trajectories and symptoms. I'm not really an expert in multiple sclerosis, but the main symptoms are neurological symptoms, vision problems, blurriness, muscle weakness, and muscle spasms, numbness of limbs, tingling, balance issues, a lot of neurological issues. And multiple sclerosis leads to reduction in quality of life, of course, but also life expectancy of reduction of approximately seven years. So MS is the most common chronic inflammatory disease of the central nervous system. It affects mostly women, so I think 70% of cases are approximately women. And just to give you an idea about the incidence, it's actually relatively high, so I have the number here for Germany. In Germany, there are 100 to 200 cases per 100,000 people. So that's not that rare. And for a long time, it was really unclear what causes this, what causes the immune system to do this. And infections were suspected for a long time. I think measles was one of the suspects that measles virus was one of the suspects at some point, but also genetic and environmentally influences probably play a role. Now in 2018, a study showed absent par virus being present in lesions in the brain of people with multiple sclerosis. So that kind of was the first hint. And then in 2022, a really great epidemiological study came out that was conducted with the US military. And so of course, the US military has very good health records of the personnel. And what was done was these researchers that looked into that analyzed data from 1993 to 2013. So it's basically 20 years of surveillance. And that data came from about 10 million active US military members and included a little bit less than a thousand multiple sclerosis diagnosis. And so they looked into all kinds of factors, all kinds of readouts. And one of the things that they found is the concentration of a protein called neurofilament, which is basically a sign of degradation of neurons. If you find that in blood, the concentration of that increased before people got multiple sclerosis. So that seemed to be an early marker of the disease showing up in progress. And they also tested, serologically so based on antibody responses when people got infected with EBV. And what they observed is that people who got infected with EBV then had basically an increase in this neurofilament protein in the serum in the blood. And they connected those two things. And then they looked how EBV infections, recent EBV infections, influenced the risk of getting diagnosed with multiple sclerosis. And what they found is that recent EBV infection and this neurofilament showing up in serum increased the risk for getting diagnosed with multiple sclerosis by 32-fold. And so that's a huge increase. And actually it's extremely rare that somebody who is Epstein-Pauver is negative gets multiple sclerosis. So that's kind of really a smoking gun there. Of course that's an epidemiological study and that's an association between risks, risk of getting multiple sclerosis and having an EBV infection. And it's not causal yet, but there's strong indication that this is actually the cause for many multiple sclerosis cases. Actually there's now also data where people looked at the potential mechanism. And it seems that if people make antibody responses to a protein that's called Epstein-Pauver and nuclear antigen A, and it looks like that if people make antibodies to an antigen that's called Epstein-Pauver, nuclear antigen 1 or Epna 1, they can produce immune responses that also cross react with neurons and that might be actually the mechanism behind that. Basically the infection triggering an immune response and antibody response that not just recognizes the virus but also recognizes the neurons and by that triggering the destruction of the neurons. So I think basically the evidence right now suggests strongly that many multiple sclerosis cases might be caused by Epstein-Pauver's infections. And that of course also makes you think about vaccine development, right? It would be good if these multiple sclerosis cases could be avoided. And so having a vaccine against Epstein-Pauver's and basically avoiding these infections would be great. But that's complicated for a number of different reasons. First of all, there's all of these different spike proteins, the virus infects many different cell types. And so you probably need to have many different types of neutralizing antibody responses to really get protected from the infection. And then making these spike proteins, for example, recombinantly, making good vaccine is really hard because there are many different ones of them, different, different complexes, right? And so one hope was that with mRNA technology, that would be easier because you don't need to recombinantly express these proteins and make sure that their fault that correct can come together in the right complexes, you can just express combinations of them as mRNA vaccine in the body of the person being vaccinated. And Moderna actually has two of these approaches in phase two clinical trials. We'll see how that progresses. I think they announced recently that you do changes how the FDA, the US government deal with mRNA technology that they wouldn't move ahead with infectious disease trials to later stage trials anymore, but we'll see what these trials bring in terms of results. And of course, it would be really good to have a vaccine that can prevent EBD infections and as a basically consequence, also prevent multiple sclerosis and maybe also some types of cancer. And we'll see if this is going to be successful. I think it's going to be challenging also because doing these trials might be challenging. One might need to use mononucleosis as primary endpoint and not multiple sclerosis because of course it takes a long time to do these trials if multiple sclerosis is standpoint and it might need massive numbers in terms of people in the trial because while multiple sclerosis is not rare, it's not super frequent either and that really makes it hard to do this at this kind of controls. Alright, a summary Epstein-Barrows is a Herpes virus that has a complicated life cycle can cause relatively unproblematic infections in very young children, can cause symptomatic disease in young adults and can contribute to severe disease including multiple sclerosis and different types of cancer and potentially also dementia and Parkinson's. We'll see if we get a vaccine against it in the future. Hopefully it's going to be possible. So that's it for today. 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