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The hidden world of human herpes viruses | Paul Moss | TEDxUniversityofBirmingham

when did you last have a viral infection maybe you had flu just before Christmas or perhaps you've got a cold there's plenty of those around well the answer is you're fighting a viral infection right now in fact you're fighting several the reason is the human herpes viruses this is a family of eight viruses and you've probably been infected with about three or four of those if not more you'll know about chicken pox varicella-zoster you've probably had that and glandular fever which many students can catch and around this age but these viruses and there is a picture of another very beautiful protein coat and inside there there's the DNA double-stranded DNA they have a number of very interesting features the first is that they are normally silent when you get these viruses you often don't know about it but you carry these viruses because remarkably they are never cleared from your body when you have flu get rid of it after a few days but these viruses you have to fight them for the rest of your life now the way that you do that is by using your immune system so your immune systems got to control cancers other infections but it has to control these herpes viruses for many many decades and we know that that's true because if we were to weaken your immune system if you have to have a transplant or take drugs then these viruses can become a real problem and they can cause disease and even death now the virus that I've been working on over the last few years it's called cytomegalovirus I didn't do a lot of greek at school but I know that Saito and megalo means cell and big and here's a picture of cells infected with site Omega right and you can see that the name is very true the cell has been infected it's taken over that cell that's making these what we call inclusion bodies generating vast numbers of new viruses to spread to the next person and that cell will be destroyed soon as it releases new viruses now about half of is or 30 to 40 percent of as a carrying CMV it's extremely common it's often transmitted by breast milk breast milk is a very good way of transmitting a virus from one generation to the next and it's almost always silent that's the conventional view that this doesn't cause a serious problem in healthy people but in patients are immune suppressed those in hospitals those having kidney transplants or bone marrow transplants this is a real threat a real killer virus and something that we need to control now it is a wonderful virus it makes 160 proteins and as I say it replicates within a cell within 24 hours but I'm more interested in how our body controls it you see I'm my research is in immunology and I'm interested in your immune system and how you fight this virus off for many many decades your immune system is made up of cells white cells are circulating in your body right now they call T lymphocytes and we know that they control the virus by constantly killing any cell that becomes infected with CMV and because we were interested in CMV in our hematology patients I was very keen to understand more about these white cells against CMV I wanted to count them to see how many they were I wanted to study their function and to use them so we had to work away work out a way that this could be done and so over ten years ago I started some work with the John Altman and Mark Davis from California and we knew that if you had a white cell against a virus it would stick to the virus so in the laboratory we can generate artificial forms the virus and stick them to these white cells but that's no good that there's no label there and doesn't tell you anything so what we were able to do then was to add a fluorescent molecule onto the virus a red protein these actually come from seaweed if you go along the beach you'll see proteins with seaweed which is very bright red and it makes these very useful proteins which fluoresce so we're able to construct this molecule with a virus and a fluorescent tag which then allows you to identify the white cells against a specific virus because they are marked they are fluorescing they're giving off this red fluorescence what we can then do is that we can take blood from anybody we can do it on you and we can stain that blood with these reagents and we can count the number of white cells that you have against any specific infection if you look at this chart behind me that's a sample of blood from a healthy person every single black dot on there is a cell it's a white cell within the blood but it's the ones on the top right which are of interest to us because they're staining red those are the white cells in this patient this healthy person in fact that are committed to fighting CMV now when we started this work people said well you know the immune response to CMV is going to be very small this is a virus that's around for decades it doesn't cause much harm the immune response will be small you won't probably see it well as you can see we are astonished when we first saw this the magnitude of this immune response against CMV is extraordinary in that case 6 percent of all the white cells but we can see levels of 10 20 30 percent or more of all white cells in blood can be fighting CMV is there is no other bacteria or virus you will ever encounter that stimulates an immune response as strong as this virus cytomegalovirus is a great surprise and it's led to lots of interesting words which work which you carry on to this day and many other groups on understanding how this happens and why it's necessary but we wanted to do more than that because we got into CMV because it was a problem in patients and with patients it's clear what's going on they are have weakened immune responses they don't have those white cells and if you don't have those white cells against CMV the virus simply replicates out of control this is a chest x-ray as you know and you'll see that those lungs at the bottom they're a little bit too white and a little bit too much cotton-wool projection on there that is pneumonia or pneumonitis inflammation of the lungs and that's due in this case to cytomegalovirus and this picture of lung inflammation has been a extremely common problem in patients who have organ transplants lung liver or particularly bone marrow as I recall stem cell transplants and in the early days of stem cell transplantation this was killing many many people was a huge problem so we now had this conundrum or opportunity that we we knew that patients after transplants were having problems because they didn't have an immune response to CMV we'd wiped it out with drugs and on the other hand we knew that healthy donors their brother or sister or people in the laboratory had an enormous immune response to the virus is there any way that we could use that by transferring cells between people and so what we did was we went back to those scans and thought well we we know that there are so many of those white cells against CMV and a healthy person can we isolate them in some way and we did that and we use magnetic beads to pull out specifically the white cells against CMV from a transplant donor now again this had never been done before but what it allowed us to do was to whenever a patient well up to CMV problem we could get the donor ring them up take blood on that day purify their cells and infuse them into the patient on the same day and I remember that day very remarkably when we've treated the first patients of course we had appropriate ethics and so forth but we didn't know exactly what was going to happen but the patient's responded very well there were no side-effects we saw control of virus which hadn't been controlled for weeks and now this approach has been used in hundreds of patients around the world and two big trials within the UK have finished very recently we'll report this year so that's been a very exciting example of taking in a basic science discovery in the blood of healthy people and using it to treat patients well that's a very nice story for those patients who have severe immune suppression but at the back of my mind I was always thinking of the question that here is a virus that's in most of the population and stimulates this huge immune response can that really be benign that must be doing something perhaps detrimental perhaps positive because it changes the immune system so much I could even take blood from you today and work out whether you've got the virus or not simply by looking at your immune system I don't need to look for the virus the fingerprint on your immune system is so strong that's induced by CMV infection so it's always intrigued by what this virus did on an epidemiological basis for human health so where do we start to look for that and what we'd noticed is that as you get older particularly into your 70s and 80s the immune response to CMV doesn't deteriorate it does quite the opposite it increases further but B people in the age of 70 or 80 where half the white cells in their blood of fighting CMV it's almost an absurd level and so we wanted to study how CMV infection affected the health elderly people healthy donors and so we worked with a group in Cambridge George Sava caryl brain and they'd studied over 500 people over a 20-year period they take them in 1990 follow them for 20 years and it's entering most people have been around the age of 70 so there been a lot of mortality and they'd look closely at mortality rate and cause of death over that 18 year period and we said to George and Carols and very very simple questions can we just have a sample of blood taken at the start of this study 18 years ago and we will separate those people who are carrying CMV infection and those who've never been infected and we'll look at their mortality over the next 18 years what did we find well what we found was something really very dramatic here is the life table or what we call a kaplan-meier curve as you can see along the bottom we've got the 18 years of follow-up in this study and on the side on the y-axis you see everybody starts at 100 everybody is alive of course at entry and then we're looking at mortality over that 18 years and we've divided this group into two the top line is those patients who did not carry a CMV infection when they enter the study in 1990 whereas the bottom line is those people who were carrying a CMV infection and you'll see that the line is dropping more quickly for patients who are carrying a CMV infection their mortality rate is increased and they are dying sooner fact the mortality rate every year was increased by 45% now the difference between these lines is remarkably four years and so what it shows is in this cohort of people within the UK at the age of 70 if you were carrying a CMV infection your life was shortened by four years so that was really very interesting and important something we wanted to do something about the question is why what was the cause of death was a cancer or chest disease or heart disease and the answer when we looked at it was the patients were having problems with their circulatory system their blood and their circulation at heart this is a magnetic resonance image scan it's it's basically a slice through the chest and you can see the great vessel there the aorta coming out of the heart and taking blood around the body and so patients are having an excess of conditions like heart failure heart attacks and strokes and so forth and in subsequent work we now know that this virus makes your blood vessels stiffer less resistant less pliable and affects blood pressure and so this is something we're now working on to understand more deeply how this happens so what can we do wasn't enough to understand how this was working we want to do something about it and so what we're now doing we're running a study within the city where we're giving healthy older people an antiviral tablet to work out if we can kill off the virus kill off the CMV and therefore reduce the immune response against the virus and so really what we're working towards which would never have predicted is an antiviral drug that can potentially improve the performance of your heart and blood vessels and prolong life so is that the end of the CMV story are we just going to get better vaccines against CMV and better antiviral drugs and eradicate it completely and consider CMV as something that has been a problem in our evolution and has no beneficial effects or valuable lessons for us well I think not let's just think of this again because here we have a virus which stimulates an incredibly strong immune response now we might think that that's bad in this case but there are many instances where you're desperate to stimulate immunity vaccine against cancer or malaria or HIV of course where we don't have any clear answers so what would happen if we were to take CMV in the laboratory and engineer it to express a certain protein a piece of HIV or a piece of malaria and then introduce it into the virus and inject that virus into a patient or a healthy donor of course now if you were to do that you would predict that that would lead to a very strong immune response against your protein of interest you might be able to use CMV as a vector for a new type of vaccine which would stimulate very strong immune responses against problematic targets and indeed a group in America has now used this approach in an animal model of HIV and it is the best candidate for providing protection in that model and is now a leading candidate for a vaccine against HIV we're working on an approach to use this as potential vaccine against cancer and there's a lot of interest now in using herpes viruses in this way so it may be that through appropriate manipulation of this virus we can take what this virus has done throughout evolution many millions of years this ability to stimulate very strong immune responses and change it to use it for our own opportunities to create new immune responses against challenging targets of the 21st century and we can't exactly throw caution to the wind in medical practice but if we were to date do that intelligently an involving society that really would be a very bold step for modern medicine thanks very much you

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