Multiple Sclerosis Discovery -- Episode 14 with Professor Gavin Giovannoni

[intro music]   Host – Dan Keller Hello, and welcome to Episode Fourteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features part two of an interview with Professor Gavin Giovannoni about the role of Epstein-Barr virus in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We've published a blog post from Christine Granfield, the founder of HealthCare Journey. Healthcarejourney.org is a website designed to help MS patients easily navigate the expanse of information about MS. In the blog post, Ms. Granfield says that HealthCare Journey is not meant to replace the doctor-patient relationship but instead provide a place where patients can find answers to questions with accurate, up-to-date information when their physician might not be available.   We published another blog post written by our intern, Cynthia McKelvey, on how to interact with the news media. News about science is often sensationalized and over simplified. But that’s all the more reason for researchers and clinicians to be media-friendly. In her post, Cynthia offers 13 tips on how to talk to reporters so you can be sure the best and most accurate information gets to the public.   Last week we interviewed Dr. Alan Thompson of the International Progressive MS Alliance about the difficulties of researching progressive MS. We published more information on the Alliance, its goals, and a full list of the 22 recipients for their first round of funding, totaling 22 million euros. To view the article, visit msdiscovery.org and visit our News Briefs section under the News and Future Directions tab.   [transition music]   Now to the interview. Professor Gavin Giovannoni from Queen Mary University in London is one of the worlds most prolific and most visible MS researchers and clinicians. He's also on the scientific advisory board for MSDF. Two weeks ago we featured the first part of my interview with him about the potential for a cure in MS. This week we’re going to discuss the roll of EBV in MS.   Interviewer – Dan Keller Professor Giovannoni, where does it come in? How has it entered the thinking?   Interviewee – Gavin Giovannoni We have a causal theory. We don't just switch on a light switch, and we've got a call that said it evolves over time. And if there's one particular thing that looks like it's got the top candidate for being a cause of MS is Epstein-Barr virus. And I think the original observation is epidemiological. People with infectious mononucleosis, which is delayed EBV infection that is symptomatic, have a higher risk of developing MS, and that's been reproduced now across many, many studies as a risk factor. But EBV infection in itself is a risk factor because if you're not infected with the virus, in other words people who don't have the virus, have a very, very low risk…it's almost a zero risk of getting the disease. So in terms of its negative predictive value – that's the strongest value we have – people don't get MS if they don't have EBV. So it looks like it’s an essential component of the causal pathway. How it's acting in the causal pathway? We don't have any idea. We just do know that if you do get EBV infection or infectious mono it's a risk factor throughout life. So in the Danish study, it shows the risk remains even when you go into your 40s, 50s, and 60s, which is interesting.   And EBV is a complex biology. We don't know where it's acting. We know it resides as a latent infection in the B cell. And what it's doing to B-cell biology is incredibly complicated. It hijacks B-cell biology, and it affects its antigen-presenting function, it affects its survival, etc. So people are targeting the B cell; I think the B cell is important. And the reason why I think the B cell is important when you look at all the most effective therapies in MS, when you put them on a chart with all the cells they affect, the only common cell to all of them is the B cell. And the link that the B cell may be the Epstein-Barr virus. And how EBV triggers autoimmunity haven't a clue. We originally thought well maybe the link between infectious mono and MS was related to HLA susceptibility. But we did a study on university students in the UK, and we showed that the HLA type that predisposes you to infectious mono is not the HLA type that predisposes you to MS. So we don't think it's at the HLA level that EBV is interacting with MS susceptibility; it's somewhere else.   The other risk factors are smoking. And when you start putting smoking and EBV and low vitamin D, which is the other environmental factor, together it looks like there's some interaction of all three components. But how they're working at a biological level that's where research needs to be done. So some people are … I think there's mimicry between EBV and myelin proteins, and there is some data that there are some antigenic epitopes in the EBV proteins and [?] antigens, which is why a lot of people are focused on CD4 cells as being the link. I'm not sure if it is the CD4. Others are focused on the CD8 cells as being the link. Michael Pender in Brisbane, Australia, thinks that Epstein-Barr virus is acting as the innate stimulus, the danger signal, that just upregulates innate immunity that then allows autoimmune responses to occur on top of that. And he thinks that's occurring in the central nervous system. That's his theory. And he thinks that people with multiple sclerosis have a deficiency of cytotoxic CD8 cells that keep the EBV virus in check. So he's now testing the strategy of trying to boost the CD8 response against EBV and kill the Epstein-Barr virus to lower the innate activation and reduce autoimmunity. That's his theory.   I wish I could tell him my theory. All I know is that the epidemiological observations are pretty standing. And you know, we probably should be doing a vaccine trial to test the hypothesis. There is a vaccine for EBV, but it's been discontinued. So GSK developed the vaccine. It wasn't that effective in stopping EBV infection, but it was very effective in preventing infectious mono. So what it did was it raised your immunity to a level that stopped you getting infectious mono, and that may be enough for MS prevention. You know, when they sold the EBV vaccine program to MedImmune, and I heard about six months ago that maybe they had stopped the program. There is no EBV vaccine program occurring in the pharmaceutical arena. There's been a recent meeting in Oxford around Epstein's anniversary because it's 50 years since he discovered the virus. And the, Harold Varmus was there, and there's a big push now for the NIH to fund a vaccine study – interesting not to prevent MS but to prevent the secondary malignancies linked to EBV. Because EBV is linked to a whole lot of hematological malignancies. So the idea there would be if you could prevent people getting Epstein-Barr you prevent a whole lot of lymphomas particularly. I'm personally a little worried about that strategy because EBV is one of our most co-evolved viruses. At a population level, it's part of our immune systems. So I actually think at a population level EBV must be doing something good for society and the population. I think it may be a link to B-cell memory or something like that.   So if we stop people getting EBV, we may be storing our problems at a population level. But until we do the trials we won't know. So we need a vaccine, and that's the way to test is EBV causal? Coming away from it, it may just be the trigger, or it may be driving the disease continuous. If that's the case, then we need to have anti-EBV drugs. And there is one being tried right now; it's called ocrelizumab. It's an anti-CD20 drug. Itself hasn't been tested as an anti-EBV drug, its predecessor, which is rituximab, is licensed as an anti-EBV. It's actually the only drug that's licensed to treat EBV. It's licensed to treat EBV associated lymphoproliferative disease, which occurs in transplant patients. It's pretty effective at switching off on that condition, and the EBV levels just plummet. A company that's developing ocrelizumab, which is Genentech Roche, wouldn’t like for me to say that it's an anti-EBV drug, but that's exactly how it may be working in MS; it may be targeting EBV. The obvious thing is to test antivirals that target EBV. There are no specific ones that have been designed for EBV, but we've got a particular drug that we would love to test against EBV because it has some activity. Trying to get the funders convinced that we should do a trial of an anti-EBV drug in MS has been difficult. I think we shouldn't ignore the EBV hypothesis, though, because the data out there is pretty compelling that it's causal. And as a community, I think we have a responsibility to test whether or not it is causal. And the only way we can do that is intervention studies – vaccines and targeting the virus with antibiotics.   MSDF It seems the geographic distribution of MS may actually be opposite say the distribution of Burkitt’s lymphoma. And what is EBV doing and how does it do it in different regions? And I wonder if that brings in the vitamin D hypothesis again.   Dr. Giovannoni MS prevalence pretty much matches infectious mono prevalence. So infectious mono has also got a gradient. The Burkitt's lymphoma thing probably that follows patterns of parasitic infection, particularly in malaria. So I think EBV probably interacts with other infectious agents, and that's one of the theories about EBV; it's not working on its own; it's working as a coinfection with another virus. The other virus that we need to talk about are the family of the HERVs, human endogenous retroviruses. Because the EBV is a potent transactivator of these viruses. In the big body of literature on HERVs being involved in MS, a lot of us think it's associative. In other words, inflammatory response triggers transactivation of HERVs in what we see as an epiphenomenon. But there are people who think it may be linked to the cause of the disease. Again the only way we can test this hypothesis is by treating people with drugs that target EBV and HERVs. Because HERVs are drugable; they are retroviruses, and you've got a whole arsenal of therapy that could target the various components of HERV biology. We should be doing trials in that as well.   Coming back to the vitamin D, there has been one small study that needs to be reproduced showing that if you do get EBV infection when your vitamin D levels are low your antibody responses are much more marked. And so there may be some link between low vitamin D and infection, but nobody has actually studied that formally, and I think it's something we tried to do with our epidemiological tools to see vitamin D deficiency or low levels makes it more likely that you're going to get infectious mono, that maybe they are interacting with each other. I don't think it's going to be as simple as that, though, to be honest with you. I think they're probably going to be working in an immunological level. I'm not sure if they're going to be causal; I think they may be associated with each other. EBV triggers a mess of lymphoid proliferation, which consumes vitamin D levels. So if you find someone with infectious mono and they have low D levels, it could be the infectious mono is reverse causation rather than the other way of causation. So we need to do that prospectively, and it's a difficult study to do.   But I think also the other thing you've got to look at is when they're starting to put all of these risk factors together in studies, and this has been mainly been done in the Scandinavian databases – and you start putting the HLA-DR15 in, the protective HLA-A2 in, the history of infectious mono, serum levels of anti-EBV antibodies, put smoking in, start putting vitamin D levels in – you're beginning to see relative up about 40. So that's a big signal to me because the doyen of causation theory, Bradford Hill, said that when you start getting relative risks above 40 that you should be thinking causation. So I'm beginning to see a causal pathway where all of these factors now are giving relative risks that are very high compared to the background population. And so, those factors must all be in the causal pathway. And the question is which one can you intervene in? And there's a few you can intervene in. But EBV is the obvious one. If you take it out of the causal pathway, you may be able to prevent this disease.   So I'm lobbying – and whole lot of us are lobbying – that we really need to get the public health community and the MS community and the virology community together so we can start thinking about prevention trials. Around about 5 to 10% of the adult population are EBV negative. But that group of people don't get MS. So that's the important factor is those people don’t get MS.   MSDF But the flip side is 90% of the population has been exposed to EBV, and most of those people don't get MS. So do you think it's all of these other cofactors you've mentioned? Whereas EBV sort of lights the fire if the fuel is there?   Dr. Giovannoni Yes, I think that's true. And Bradford Hill, I mean he developed his theory for causation around common manifestations or re-exposures. Like asbestosis is one of the examples he always used that if you had asbestosis, which is quite of a rare exposure, the chances of getting mesothelioma, which is a rare cancer, was almost 200 times background. So that's easy to understand. But EBV is such a common exposure, and MS is a relatively rare manifestation. So in that situation, the relative risks come down. So even though the relative risk of getting MS is only about 2.2 to 2.5 with infectious mono, it doesn't mean to say it's not causal. It could still be causal. So I'm not worried that the relative risks are low. But I agree with if it's EBV infection on top of something else the genetic susceptibility, the low vitamin D, or all those other factors that then triggers the autoimmune response.   But if EBV is a pivotal factor and you stop it, those other factors are irrelevant. That's why we need to do prevention studies. We need the vaccine, though. The original vaccine strategy was developed to prevent EBV completely; that's in terms of oncoprevention. But in terms of MS and autoimmunity, you may not have to prevent Epstein-Barr virus. Maybe what you need is to make sure you're vitamin D replete and get wild-type infection when you're very young. That may be sufficient to lower the risk of MS. You may not necessarily need a lifelong protective immunity against Epstein-Barr, but maybe you just need to be infected at a young age when your immune system can deal with it. It doesn't fertilize the field for autoimmunity later on in life; that may be the strategy.   MSDF Does it get into the possibility of tolerance?   Dr. Giovannoni Yes.   MSDF To EBV?   Dr. Giovannoni If we knew about the biology of EBV, I mean I'm not a virologist. And when I delve into the complex biology of Epstein-Barr virus, how it's fooling the B cell into surviving longer and bypasses B-cell signaling pathways, it's a credibly cleaver virus. And there's a lot of biology there that needs to be picked apart in the MS field. So there may be pathways in the EBV biological pathway that could be targeted rather than just targeting the virus itself. So I think there's lots of research to be done. This is why we, as an MS community, really need to bring virologists into the community as much as possible. And at the moment, that doesn't seem to be happening a lot. There's very few virologists interested in MS. You can count them on one hand to be honest with you that are really interested in MS. Most virologists are working on other diseases. And when you go to them, it's hard to get them interested in MS because MS is something on the periphery of their thought. They're usually targeting obviously infectious diseases. But most of the EBV virologists are working in oncology, lymphomas.   MSDF Very good. Thank you.   [transition music]   MSDF Thank you for listening to Episode Fourteen of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].   [outro music]