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

00:00:06: Basically, once you infect it.

00:00:08: You don't get really rid of this virus anymore.

00:00:11: as they say herpes viruses are forever like diamonds.

00:00:28: Virological with Florian Kramer.

00:00:41: Welcome to the week's episode of virological.

00:00:44: This was recorded on March eighth of twenty-twenty six in Helsinki In Finland.

00:00:50: Today we're going to talk about The Epstein Bar Virus or EBV?

00:00:56: Jeffrey Epstein will get to the name a little bit later.

00:00:59: We used to joke that we would open up bar for virologists, it's called The Epstein Bar.

00:01:05: unfortunately its not funny anymore since all these Epstein stories came out.

00:01:10: but the virus itself is really important and interesting.

00:01:15: It has been implicated as one of causes multiple sclerosis.

00:01:19: very recently so well were going to discuss this.

00:01:23: The virus is a double-stranded DNA virus, belongs to the herpesviruses.

00:01:28: Herpesvirus is large group of DNA viruses with number members that are medically relevant.

00:01:34: We'll talk more about them in future.

00:01:40: and these viruses have relatively large genome compared to the viruses we've discussed so far.

00:01:48: So Epstein Bavaris has a genome of about hundred seventy thousand base pairs, so one hundred and seventy thousand nucleotides.

00:01:56: And just as comparison that's about ten times as much as Influenza A in terms of genome size It does code for a lot of proteins but eighty different proteins twenty, two hundred eighty nanometers in diameter.

00:02:14: So that's actually not too big.

00:02:16: you would expect it.

00:02:17: if there is a huge genome maybe its bigger but does have complicated structure and again produces alot of proteins when it infects our cells lot different ones In terms the structure.

00:02:29: on inside we have DNA genome double-stranded DNA genome associated with nuclear capsid protein then thats surrounded by Degament Protein regimen protein, which is basically similar to matrix protein in a way.

00:02:46: And then on the outside we have lipid envelope and in this lipid envelop you have number of different glycoproteins, number of difference.

00:02:55: spike proteins so lot of viruses that usually deal with one or two spike proteins.

00:03:02: SARS-CoV-II has one spike protein.

00:03:04: influenza is hemagglutinin and noraminidae but Epstein-Barr virus has a lot of different glycoproteins.

00:03:12: They're called GH, so G for glycoprotin, GH, GL, GB, GM, GN, GP-Forty-Two, GP Fifty, GP Two-Twenty and that already indicates that it's a complicated virus in which there is a complicated life cycle.

00:03:29: In fact these different glycoprotein, these different spike proteins and complexes of these proteins together may facilitate, or do facilitate infection of different types of cells.

00:03:43: And binding to different receptors on this different type of cell.

00:03:48: So some of the receptors that the virus binds to are CD-I, MHC-II which is a major protein in the immune system, complement receptors, integrins

00:04:00: etc.,

00:04:00: but it's really dependent what kind of receptor the virus is using.

00:04:07: The interesting part here, also that we have complicated infection cycle with a primary infection and then you also have persistent infections.

00:04:18: basically once infected You don't get really rid off this virus anymore.

00:04:22: as they say herpes viruses are forever.

00:04:25: It's like diamonds.

00:04:27: And so during the primary infection, the virus infects most lepetilial cells and it replicates in these cells right?

00:04:34: It goes in.

00:04:35: It starts virus production a more viruses produced.

00:04:39: at some point this virus is die... ...and the virus spreads to other cells and that's what you call the lytic cycle.

00:04:46: So it lices these cells but for example when it infects B-cells.. ..so B-Cells are major immune cell that makes antibody then starts the infection, but it doesn't actually produce more virus.

00:04:59: It does not actually produce a lot of its own proteins can stay dormant there and that's what we call called a latent infection And so I can do that.

00:05:09: basically at some point in time it can wake up be reactivated then this can turn on a lytic cycle and then viruses produced.

00:05:18: But you can stayed dormant for very long times in B cells and the immune system doesn't really see it there.

00:05:25: So how does this work?

00:05:28: Basically, the virus generates or the virus integrates itself into the nucleus of the cell so not in to our genome like HIV would do but you just basically deposits a copy of its genome.

00:05:43: circular DNA copy acts like an extra chromosome, basically.

00:05:50: So that's there in addition to our chromosomes and That's called an episome.

00:05:55: And that's how it stays there.

00:05:57: It is not completely silent.

00:05:59: In a way...it actually changes the B-cell biology A little bit.

00:06:03: so it immortalizes these b cells..and also changes their gene expression a little through epigenetic changes.

00:06:10: and thats not great because you don't want cells in your body to be immortalized, that means they don't die anymore.

00:06:17: That's not good.

00:06:18: You want yourselves at some point to die because otherwise They might become cancerous cells.

00:06:24: and it can happen here.

00:06:25: And the same is true for these epigenetic changes.

00:06:28: It means that the expression of the B cell proteins changes and that can also change cell behavior.

00:06:34: So that's another thing.

00:06:36: but the virus also uses that To you know get distributed all over the body with this circulating b-cells.

00:06:43: By the way, this infection is actually very common.

00:06:47: About ninety to ninety-five percent of adults are globally infected with Epstein bar virus and most of them don't have symptoms but they carry the virus and can actually pass it on.

00:07:00: So going back a little bit history The name comes from Sir Michael Anthony Epstein and Yvonne Barr.

00:07:10: The two of them discovered the virus in nineteen sixty-three.

00:07:14: And that's actually an interesting story.

00:07:18: Michael Anthony Epstein was listening to a scientific presentation by Dennis Barson.

00:07:23: Burkitt, A clinician who worked in Uganda Who was interested in lymphomas Burkett lymphoma is named after him and Epstein asked Burkatt if he could get samples from some of his patients.

00:07:38: and so Burketts sent samples to England where Epstein and Barr worked in nineteen sixty three.

00:07:46: And then they found the virus in these samples, that's why the viruses caused Epstein-Barr virus.

00:07:54: What does the virus do with our body?

00:07:56: How did we even get infected?

00:07:58: Typically you can get infected through respiratory droplets or through smear.

00:08:03: infections contact direct contact without a people bodily fluids sexual contacts And the primary disease that is associated with Epstein-Barr virus infections, it's known as mononucleosis.

00:08:21: A lot of people get infected when they're kids and then these infections are often asymptomatic.

00:08:28: The kids don't even get mono.

00:08:30: they often get infected in kindergarten and daycare settings, where there's a lot of interaction.

00:08:36: A lot playing, a lot touching potentially also an exchange of bodily fluids through saliva all kinds other interactions that you might have.

00:08:49: so if it happens then typically there are no symptoms when the kids are infected.

00:08:55: A proportion of individuals make it without infection throughout early childhood And they get infected during adolescence and poverty.

00:09:05: That often leads to symptomatic infections, this happens with the first sexual contact or kissing... ...and that's also why it is called kissing disease sometimes!

00:09:16: Here these symptoms are often fatigue, fever, swollen lymph nodes,... ...and large spleen.

00:09:23: This can last quite some time and lead to chronic fatigue.

00:09:27: A colleague of mine had that.

00:09:29: He was actually older, he was in his early thirties I believe and... ...he was really without energy for a very long time right?

00:09:38: So this virus really trains your energy And makes it hard to be productive.

00:09:44: The enlarged spleen is also interesting and that can be problematic because if the spleen is enlarged, then you have an accident where your fall or something like that.

00:09:55: The spleen can rupture and it's highly problematic And so those are normal consequences of an Epstein-Barr virus infection.

00:10:05: Typically we make immune response at some point and the virus goes into hiding Because they're circulating neutralizing antibodies So basically becomes latent just stays there.

00:10:17: But the problem is that the virus, because it does what it does... ...it can immortalize cells.

00:10:22: It changes cell's behavior and also associated with different types of cancer including different type of lymphoma gastric cancer nasopharyngeal cutcinoma And this is problematic.

00:10:40: unfortunately in some cases the outcomes are not great.

00:10:47: There is also a connection to dementia and Parkinson's although that not hundred percent clear but it seems the virus plays role there as well.

00:10:57: And interestingly, it can also be found in tumor cells of breast cancer.

00:11:01: 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 EVV.

00:11:11: That's why they are positive.

00:11:12: so i think their idea here is not EVV which causes the cancer initially.

00:11:19: So as mentioned ninety-to-ninety five percent of individuals are infected.

00:11:26: you know, immunity typically is induced after the primary infection and so the virus goes latent.

00:11:33: Goes into hiding... One thing is this latent phase in the hiding of the virus in the nucleus In terms of depositing its genome as an episome on the nucleus but it's also very good at dealing with diesel responses And basically surviving D-cell surveillance, so it's really good in undermining the immune system.

00:11:59: Something that was found more recently in the last few years is a strong connection to multiple sclerosis.

00:12:07: Multiple scleroses are pretty bad autoimmune disease where an immune system attacks myelin sheets on nerve cells.

00:12:18: So basically the immune systems slowly destroys nerve cells.

00:12:25: These myelin sheets, these are basically protein sheets that cover nerve cells on the outside kind of insulation of neurons and you can imagine if that surface gets destroyed they might not work well anymore.

00:12:44: And so multiple sclerosis has different disease trajectories and symptoms.

00:12:49: I'm not really an expert in multiple scleuroses but you know the main symptoms are neurological symptoms, vision problems, blurriness muscle weakness and muscle spasms.

00:13:02: numbness of limbs tingling balance issues a lot of neurological issues.

00:13:08: And multiple sclerosis leads to reduction in quality life but also life expectancy.

00:13:21: MS is the most common chronic inflammatory disease of the central nervous system.

00:13:27: It affects mostly women, so I think seventy percent of cases approximately are women.

00:13:33: and just to give you an idea about incidents it's actually relatively high.

00:13:37: So i have a number here for Germany.

00:13:40: in germany there hundred to two-hundred cases per hundreds thousand people.

00:13:50: For a long time it was really unclear what causes this, right?

00:13:54: What causes the immune system to do this.

00:13:57: And infections were suspected for a long term.

00:14:00: I think measles virus was one of the suspects at some point but also genetic and environmental influences probably play a role.

00:14:10: Now in two thousand eighteen studies showed epsin bar virus being present in lesions, and the brain of people with multiple sclerosis.

00:14:21: So that kind was a first hint.

00:14:24: And then In twenty-twenty two really great epidemiological study came out That was conducted with US military.

00:14:32: The US military has very good health records Of their personnel.

00:14:38: And what was done, these researchers looked into that analyzed data from the year of three to two thousand thirteen.

00:14:46: So it's basically twenty years of surveillance and their data came about ten million active US military members included a little bit less than a thousand.

00:14:59: multiple sclerosis diagnosis They looked into all kinds of factors, zoological is so based on antibody responses when people got infected with EBV.

00:15:38: And what they observed was that people who got infected then had basically an increase in this neurofilament protein, in the serum and blood... ...and connected those two things.. ..and looked at how recent EBV infections influence the risk of getting diagnosed with multiple sclerosis.

00:16:03: And what they found is that recent EBV infection and this neurofilament showing up in serum increased the risk for getting diagnosed was multiple sclorosis by thirty-two fold, so thats a huge increase!

00:16:19: Actually it's extremely rare.

00:16:24: Epstein-Bauer as negative gets multiple sclerosis.

00:16:27: So that's kind of really a smoking gun there, Of course That is an epidemiological study and it's association between risks of getting multiple sclorosis And having a fresh EBV infection.

00:16:42: It isn't causal yet but they are strong indication this actually the cause for many multiple sclerozes cases.

00:16:50: Actually there's now also data where people look at the mechanism, a potential mechanism and it seems that if people make antibody responses to a protein its called Epstein-Bar nuclear antigen A. And It looks like that If People Make Antibodies To An Antigen Its Called Epstein Bar Nuclear Antigen One Or Epna one They Can Produce Immune Responses That Also cross-react with neurons and that might be actually the mechanism behind it.

00:17:24: Basically, the infection triggering an immune response in antibody response to not just recognize as the virus but also recognizes the neurons by that trigger the destruction of their neurons.

00:17:40: so I think basically the evidence right now suggests strongly that many multiple sclerosis cases might be caused by abstinence bar virus infections.

00:17:51: And of course also makes you think about vaccine development, it would be good if these multiple sclorosis cases could be avoided and so having a vaccine against the abstinance bar virus.

00:18:04: basically avoiding this infection is great but thats complicated for a number different reasons.

00:18:12: First of all, there's all these different spike proteins.

00:18:16: The virus infects many different cell types and so you probably need to have many different types of neutralizing antibody responses really get protected from the infection.

00:18:28: And then making this spike protein for example recombinantly Making good vaccine is hard because they are at many different ones in different complexes.

00:18:40: One hope was that with mRNA technology, That would be easier because you don't need to Recombinately express these proteins and make sure they are folded correctly And come together in the right complexes.

00:18:53: You can just Express combinations of them as mRNA vaccine In the body Of a person being vaccinated.

00:19:00: And Moderna actually has two of These approaches in Phase II clinical trials.

00:19:05: We'll see how it progresses.

00:19:06: I think They announced recently To do changes how the FDA, their US government deal with mRNA technology that they wouldn't move ahead with infectious disease trials to later stage trials anymore.

00:19:19: 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 EBV infections And as basically consequence also prevent multiple sclerosis maybe some types of cancer.

00:19:39: we'll see if this is going to be successful.

00:19:42: I think it's gonna 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 takes a long time To do those trials with multiple sclerozes at the end point And you may need massive numbers in terms people on trial because while multiple Sclerosis isn't rare It's not super frequent either and that really makes it hard to do these clinical trials.

00:20:15: All right, a summary of Epstein-Bauvirus is the herpes virus has complicated life cycle can cause relatively unproblematic infections in very young children... ...can cause symptomatic disease in young adults.. ..and contribute severe diseases including multiple sclerosis and different types of cancer And potentially also dementia and Parkinson's.

00:20:43: We'll see if we get a vaccine against it in the future, hopefully its going to be possible!

00:20:48: So that is for today.

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