Understanding Hepatitis C

06 December 2009
Presented by Chris Smith, Kat Arney.

Join us to explore the virus behind Hepatitis C. We'lle be investigating the causes, prevention and treatment of this often masked but serious disease.

In this episode

20:12 - Hepatitis C Virology

Joe Grove discusses the sneaky ways the Hepatitis C virus evades our immune system...

Hepatitis C Virology
with Dr Joe Grove, Birmingham University

Chris -   With us this week is Dr. Joe Grove who is a hepatitis researcher.  He's from Birmingham University and he works on the way that hepatitis C viruses actually get into our cells and then escape from the immune system.  One of the things about hepatitis C is once you've got it, in the majority of cases, you don't actually get rid of it again.  It stays with you, which means it must be able to get away from the immune system.  Joe, how are you?

Joe -   Hi.  How are you?

Chris -   Very well.  Welcome to The Naked Scientists.  So tell us a little bit first of all about what actually is hepatitis C.

Histopatholgical image of hepatocellular carcinoma Joe -   Okay.  It's quite a common misconception that hepatitis C is some way related to the other hepatitis viruses.  So it's good to start and establish that it isn't.  The word hepatitis is derived from the latin for liver.  So the hepatitis viruses share one thing in common.  They infect the liver.  However, in the same way that you could describe a crab, a dolphin and a jelly fish as ocean creatures, these viruses are completely different but they just share a habitat.  With hepatitis C, if you look at its closely related viruses, they are viruses such as dengue virus which transmits between humans via mosquitoes, and there's also pestiviruses which are related that infect cattle.  Hepatitis C seems to be quite the black sheep of the family within this group and it's quite unusual in that it can only be found in humans.  Although as Henrik eluded to earlier, you can get infection of chimpanzees as well.

Chris -   How does it spread in the majority of cases?

Joe -   It's a blood-borne virus and we only first isolated the virus in the last 20 years and that's allowed research to start.  Before that, we didn't know what caused this form of hepatitis and it was actually transmitting, certainly in the western world, predominantly through blood transfusions.  Much the same way that HIV was in the '60s and '70s.  However, since we've discovered what the virus is, we can test blood so there's no danger from blood products, certainly in the western world.  And now, the predominant route of transmission in the western world is via intravenous drug users sharing needles.  However, in the developing world, there is a problem with poor medical practices and poor sterilization of medical implements, leading to transmission.  So for instance, in parts of Egypt, you have a very high level of infection because of a vaccination campaign where the needles weren't sterilized properly, and as a result, 40% of the population contracted hepatitis C.

Chris -   Yes, I think that the current numbers are 1 person in 10, if you just pick a person at random, has actually got it.  Does the virus then just home in on the liver or does it affect other tissues too?

Joe -   Well, there is some evidence to suggest that the virus may have reservoirs throughout the rest of the body but the predominant site of replication is within hepatocytes.  These are the cells that function within the liver.  So, once the virus enters the bloodstream, it will circulate in the blood, interact with a specific receptors expressed on hepatocytes and enter liver cells.  This is the place where it replicates.  Viruses are one of the most simple forms of life and they are completely dependent on Human Livertheir host.  So the entry of a virus into its host cell is a prerequisite for its replication.

Chris -   So in other words, it gets into the liver cell, hijacks it, turns it into a hepatitis C factory, and then that hepatitis C infected cell just makes more copies of hepatitis C which then goes around the bloodstream, infects other liver cells, but can also - if someone sticks needle in there, and then shares that needle, infect another person.  But the key thing is, there are many different types of hepatitis virus, but they don't cause an infection for life.  But hepatitis C does.  So, why is that?

Joe -   You're right.  It's peculiar in this sense.  It seems particularly able to evade the immune system.  There seems to be lots of reasons for this namely - to start with, hepatitis C is what is known as an RNA virus.  That is, it's genetic material is made of a chemical related to DNA, called RNA. However, this RNA has a higher mutation rate.  Therefore, the virus can change more quickly than a DNA organism.  And this allows it to stay one step ahead.  It's continually evolving to evade the human immune system.  However, it also seems to be able to perform other tricks.  For instance - the lab I work in with Professor Jane McKeating in Birmingham, we've been looking at some of the ways that the virus may evade the immune system.  The virus can interact with B cells and these are cells of the immune system, and it seems like it can be transmitted within these B cells.  So it hides within them as kind of a 'Trojan horse' model of transmission.  And also, some of the work we're doing would suggest that the virus can transmit directly between cells, avoiding the immune system that's in the bloodstream.

Chris -   So although, if you look at people's blood who have hepatitis C, you can find lots and lots of antibodies against HVC, because the virus may not necessarily be in the same blood space as those antibodies, they can't actually neutralize it?

Joe -   Yeah.  It's very complicated.  We can take the blood of infected individuals and take the antibodies from these individuals.  And they seem to show activity in the lab.  We can show that we can stop a virus in the lab.  However in that patient, that antibody doesn't help them in any way.  It may help control the virus, but it doesn't help them resolve the virus.  So we are particularly interested in how this is achieved and in particular, we're looking at the entry of the virus, and this is the stage at which neutralizing antibodies act.  So a neutralizing antibody will stick to the surface of hepatitis C, and in doing so, inactivate the glycoproteins which are the proteins that sit on the virus and interact with the receptors that are on the cell.

Chris -   So the point we're getting to is what we need if we want to protect people is we've got to have antibodies in the bloodstream before someone gets infected, so that they can interrupt that process upstream of the virus actually getting into cells because once it does, that is probably too late then.

Joe -   Yes, correct.  It's important that we identify which regions of the virus are important for the entry into the cell.  So, you will raise antibodies against lots of different parts of the virus, but some of those are decoys.  Some of those are red herrings so that the immune system follows this particular part of the virus and it won't help them at all.  So, we need to identify which regions of the virus are important for neutralization as well.

28:34 - What causes Red Eye in Photographs?

What causes Red Eye in Photographs?

Red eye occurs because when you take a flash photograph - the camera produces a big burst of light to illuminate the subject and that burst of light goes in through the open pupil of the subject, and bounces off the back of the eye. There's a layer called the choroid which has a very rich blood supply inside the eyeball and that reflects red light, the colour of the blood, back out of the front of the eye and into the camera. This happens so quickly that there's not time for the pupil to contract before the camera takes the picture. So you see this red reflection of the interior of the person's eyeball. Red eye reduction works by the camera shining a brightish light or doing a few 'spoof' flashes at the subjects first. This constricts the pupil down in the people you're taking a picture of, and then it takes the proper picture. This means that there's a very small aperture in the front of the eye as the pupil has got very tiny, therefore much less light gets in and it's much harder for light to reflect back out again. And that's how red eye reduction occurs.Why are some people more prone than others? Perhaps, the pictures that you've been taken in are not pictures involving flash photography, so you don't seem to have the effect. Perhaps also, you're not directly in line with the camera flash. If the flash didn't actually illuminate the eyeball sufficiently on its interior, not enough light will come back out of the camera. One other possibility is that you have very, very dense pigment epithelium. This is a layer of melanin (the same stuff that gives you a sun tan) inside the eye and that's what soaks up some of the extra light. People also naturally differ in how wide their pupil is in any particular light. People with wider pupils are more likely to end up with red eye in photos, whereas those with smaller pupils are less likely.

30:33 - Safer Blood Transfusions

Meera Senthilingam investigates how safe the blood we receive in transfusions really is...

Safer Blood Transfusions
with Jean-Pierre Allain, University of Cambridge & Lorna Williamson, NHS Blood and Transplants

Meera -   Until 1991, blood transfusions were a common cause of hepatitis C infection, as the virus is spread by blood to blood contact.  Famous figures such as the late Anita Roddick, founder of The Body Shop and stuntman, Evel Knievel were believed to have contracted hepatitis C in this way.  But since 1991, the virus has been screened for in all blood donations in the UK.  So just how do our blood services screen for not only this virus but other infectious agents as well?  And as a result, how safe is our blood?  To Bags of blood collected during donation, showing dark colour of venous blood.find out, I spoke to Jean-Pierre Allain, Professor of Transfusion Medicine at the University of Cambridge.

Jean-Pierre -   Actually, we screen essentially for viruses and there are three main viruses we are screening for.  The first one and most well-known is HIV, the second is hepatitis B virus or HBV, and the third one is hepatitis C virus or HCV.

Meera -   How do you actually go about testing for these blood samples?  So, somebody comes in to give a donation, what happens?

Jean-Pierre -   First, we ask the potential donors to fill a questionnaire regarding potential infections and we also ask questions about their sexual behaviours because it has to do with the higher risk of infections, and also about drug abuse.  Then we collect two tubes of blood, one with which we test for evidence of viral infection, essentially antibodies to HIV and HCV, and for hepatitis B surface antigen.  In addition to that, with the second tube, we test for the genome of the virus.  In other words, a direct gene or nucleic acid of the virus.

Meera -   How do you actually go about looking for antibodies in somebody's blood and what does this tell you then about their infections?

Jean-Pierre -   When we test for antibodies, we are looking to determine whether the individual has been in contact with the virus or not.  We detect these antibodies by capturing the antibodies on a range of antigens from the virus itself.  If the antibodies are present, they are binding to these antigens and then we detect the presence of antibodies.

Meera -   What then happens in the next step where you start looking at the genomes of these viruses?

Jean-Pierre -   Every blood sample is tested for this genome.  Actually, not individually like we do for antibodies, but in what we call pools of samples from the donors - at the moment, this pool is 24.  When we test for the genome in these pools of 24 and we find a positive reaction, then we go back to the individual donations to identify which donor is responsible for the pool being positive.  Then we correlate that with the antibody being found separaTaking a blood sampletely.

Meera -   Now I imagine when looking for particular genomes of the virus, it must be quite difficult because viruses evolve very rapidly.  So, which part of the genome do you look at?

Jean-Pierre -   The virus itself has a tendency to easily modify its genome.  So eventually, it could be difficult to detect.  Except that we choose an area of the genome we know is what we call conserved which mean that it doesn't change at all or very little.

Meera -   Why is this area conserved?

Jean-Pierre -   Because it's functionally critical.  And the more critical it's functionally for the virus to replicate, the more it needs to stay the same.

Meera -   Now, having done all of these tests and looking into the blood, what is the risk of somebody now who receives a blood transfusion receiving infected blood?

Jean-Pierre -   If we talk about the hepatitis C virus and HIV, the risk is calculated at about 1 in 3-5 million which means that it's less likely to be infected than being hit by lightning if you stroll on a Sunday afternoon.

Meera -   Jean-Pierre Allain from the University of Cambridge.  So we now know how we screen for viruses that we know of and know the biology of, but what about infections that we haven't met before?  What about the unknowns?  I asked Lorna Williamson, Medical and Research Director for NHS Blood and Transplants.

Red Blood CellsLorna -   Virtually every blood donation that's collected is separated into different parts.  When people say blood transfusion, they generally mean the red blood cells which are given to carry oxygen and treat bleeding and severe anaemia.  But we also can take the plasma, the liquid part of blood, and that is used to replace clotting factors in patients who are bleeding, and then finally, we can make blood platelets which are little discs that circulate in the blood and they are also important to prevent bleeding.  We try as hard as possible to remove all the parts of blood that won't benefit the patient.  We filter out the white blood cells which, in a transfusion, don't offer any benefit.  If the patient needs red cells, we will take away all the plasma and we can give the patients exactly what they need and no other part of the blood.  And then where we can, we would alter the blood donation in some way to try and kill or remove any viruses or infectious agents.  So for example, plasma can be heat treated or treated with chemicals and there are new methods coming through to treat platelets with chemicals to kill viruses and bacteria.

Meera -   How does treating them with heat help make them safer and remove any viruses?

Lorna -   Well it simply prevents the virus genome from replicating.  It destroys the ability of the DNA and RNA to copy itself, so the virus can't multiply.

Meera -   As well as heat treatment.  What other precautions that are taken?

Lorna -   What we would really like would be a method of either heating or treating with chemicals the red blood transfusions which are the biggest type of blood product that's used and such methods are in development.  The one thing we are assessing for blood transfusions are new filters to remove infectious agents called 'prions.'  They're small bits of protein that cause prion diseases like variant CJD and BSE in cattle.

Meera -   And what do you think, just lastly then, the kind of risks are of any infection or viruses that you just really aren't aware of at the moment and how prepared do you think the system is to deal with this?

Lorna -   So we work very closely with the Health Protection Agency where the monitoring systems for infections that may come to this country from elsewhere in the world.  Swine flu is a good example of that.  There are also systems for monitoring infections in farm animals and we work very closely with other blood services throughout the world.  With migration and international travel, infectious agents can move around the world very rapidly.  So, it is a case of maintaining high vigilance on an international level.

38:47 - Hepatitis C in the Clinic

Graeme Alexander explains the effects of Hepatitis C on the body adn the current methods of treatment against the virus...

Hepatitis C in the Clinic
with Dr Graeme Alexander, Addenbrookes Hospital

Kat -   What does Hepatitis Cactually do to the body, and how can we treat it?  It's now time to find out from Dr. Graeme Alexander, he's a Clinical Hepatologist at Addenbrooke's Hospital.  So, hello Graeme.  Welcome to the show.

Graeme -   Hello.

Kat -   Now, just before we start, we've had a quick question from SecondLife, from Dali Waverider.  He wants to know how many classes of hepatitis virus are there and how are they different?

Graeme -   Well a lot of viruses can affect the liver, but there's five that we recognize as important in the liver and they're Hepatitis A, B, C, D, and E - rather imaginative aren't we?

Kat -   Fair enough.

Human LiverGraeme -   The most important thing about hepatitis C is that it, by and large causes an infection that lasts for a lifetime while the other viruses don't (usually).  So that differentiates it quite easily.  And it's an RNA virus whereas hepatitis B is a DNA virus infection.  But that's a semantic difference.  The important thing about hepatitis C is that it causes lifelong infection in many people.

Kat -   So let's look at this kind of infection.  So we've discovered that it goes in to the cells in the liver  and it sort of turns them into little virus factories.  What effect does that actually have on the liver?

Graeme -   Well I think the most important thing to stress straight away is that for most people, you don't know you've got hepatitis.  It doesn't cause liver damage in the majority of people.  But about 5%, perhaps as high as 20%, of people in some populations get into a situation where they develop liver damage.  And you might not know you've got liver damage evolving until maybe 50 or 20 years after you've been infected with the virus.  In a way, the virus wears the liver down over a period of years, causing scarring within the liver and once the scarring is present, then the patient is at risk of liver failure and the complications thereof.

Histopatholgical image of hepatocellular carcinoma Kat -   So presumably, there must be something to do with the differences between people, as to why some people are susceptible to having liver damage from hepatitis infection and why some people aren't.  Do we know anything about those kind of genetic factors?

Graeme -   Well, we do.  We know quite a lot about those genetic factors and we know that for example, men do much worse than women.  We know that it matters how old you are when you catch the virus.  Men who are over 40 when they catch the hepatitis C do very much worse than say, a young girl of 20 who catches the virus.  We know that people who are overweight do very much worse than the patients who are thin, and we know that people who drink heavily increase their risk of liver damage from hepatitis C very, very much so.

Kat -   And this, we bring in a little question here from Meera Maquana who says, "Why does chronic liver disease, and things like chronic drinking, lead to cirrhosis and what's the process of this scarring that's going on?"

Graeme -   The liver cells are part of a complicated organ - the liver - where there's lots of different types of cells.  There's another cell sitting next to the liver cell called a stellate cell and there are signals sent out by an injured liver cell to those stellate cells which scar the liver.  So the liver ends up being scarred in exactly the same way as someone who's had an operation and there's a scar on their skin, but this scar is spread finely and diffusely throughout the whole liver.

Kat -   Now, something I do know from my work at Cancer Research UK is that rates of liver cancer are going up and we know also that liver cancer is linked to hepatitis infection.  How does that work?  What's the link there?

Graeme -   Well it's all through liver disease.  All forms of liver disease predispose Secondary tumor deposits in the liver from a primary cancer of the pancreaspatients to liver cancer in the longer term and it's one of the things that we take great care for is to look for liver cancer at an early state to try and pick it up.  Hepatitis C is one of the major causes of liver disease in this country.  So it's now one of the major causes of liver cancer.  And if you have advanced liver disease, you've got a one in four risk of getting on to get liver cancer subsequently.  It's also a significant problem.

Kat -   So, it strikes me.  Is that it's fairly important to try and treat, and probably even prevent hepatitis infection.  Where are we currently with treatments?  And we've heard already about some current ideas, you know, this microRNA drug for future treatments, but where are we currently with treating hepatitis?

Graeme -   Well, there's been enormous progress in the last four or five years.  We've been known about interferon which is what you and I produce when we get an infection, flu for example.  We've known about that for quite a time and on its own, it didn't really work very well.  And then another drug called 'ribavirin' was introduced, but that on its own didn't do very well either.  But when we combined these two drugs, we got striking improvements in response rates which was unexpected, but very gratifying.  So now, we think that we can treat something towards about a half of the patients that come to see us.  But the most important point to stress here is that the earlier we treat the patients, the better, so younger patients did much better with treatment than older patients.  So it's quite important that we do see people at an early stage and we can consider treatment as early as possible in the course of the disease.

Kat -   And do we already have vaccines against hepatitis C? What hope is there for preventing the transmission of it?

Graeme -   Well, hope is all we have at the present.  There are a lot of people working on this area and you've heard from Joe Grove earlier about the virus evading the immune responses and the number of tricks that it has to do this.  The problem we face at the present is we don't recognize the population who are immune to hepatitis C in the long term.  They don't develop neutralizing immunity and if you can't develop neutralizing immunity, it's very hard to see how you would target a vaccine response.  So sadly, I think, vaccine responses are some distance away and we're really looking at prevention for now rather than a vaccine.

41:17 - How does liver disease lead to cirrhosis?

How does liver disease lead to cirrhosis?

We put this to Graeme Alexander:Graeme - The liver cells are part of a complicated organ - the liver - where there's lots of different types of cells. There's another cell sitting next to the liver cell called a stellate cell and there are signals sent out by an injured liver cell to those stellate cells which scar the liver. So the liver ends up being scarred in exactly the same way as someone who's had an operation and there's a scar on their skin, but this scar is spread finely and diffusely throughout the whole liver.

44:36 - Cycle Centrifuge

Cycle Centrifuge

52:06 - Can Hepatitis B be transferred in urine?

Can Hepatitis B be transferred in urine?

We put this to Graeme Alexander:Graeme - When I meet patients in the clinic, I get two types of question. One, from a patient who's scared that they'll transmit hepatitis B to someone they love - and then the other, from the person that they love, wondering if they'll catch it from their partner. And the answer is that you can't catch hepatitis B from urine. These viruses are actually quite difficult to catch, both hepatitis B and hepatitis C. And hepatitis B is acquired largely by contact with blood or through sex and hepatitis C pretty well only by contact through blood. So, you can live with someone for many, many years and not catch hepatitis B or C from them because close contact in the family situation is entirely safe.Chris - And I think the other mitigation is that there is a good vaccine for hep-B, isn't there? So if we identify people in a family situation who have one carrier and one person who isn't infected, we can vaccinate the uninfected person to protect them.Graeme - It's probably the most effective vaccine that we've ever come across, very effective and very safe once you've been vaccinated.

53:23 - Does money carry germs?

Does money carry germs?

Yes, certainly money can be a vector for infection and as an example, lets look at norovirus, which causes winter vomiting disease (but more recently, vomiting all around the world at all times of the year - it's becoming incredibly common). Norovirus is a tiny particle, one 30,000th of a millimetre across, can very easily be transmitted from one surface to another. They can survive seven changes - so if you touch something, and someone else touches it and picks it up, they can then transfer it seven times and the virus still remains infectious. You only need to pick up one of them to get infected. Yuck!

54:14 - How do farmers propagate seedless crops?

How do farmers propagate seedless crops? What do you have to plant to grow a seedless grape? How do these, and all the other seedless fruits, get sown in the first place?

How do farmers propagate seedless crops?

We put this question to Stephen Tomkins, from Homerton College, Cambridge, and Jennifer Schultz Nelson, Horticulture Educator with the University of Illinois: Stephen - You need to know something about why they have no seeds and that's because they're often triploids. That is, they've got three sets of chromosomes and you and me have two. And when it comes to sexual cell divisions in meiosis, they can't organize their chromosomes properly and they fail, and therefore, they have no babies. So the question that you want answered is how do you get to a triploid fruit? And the answer to that is a little bit complicated. Most plants have two sets of genes, two sets of chromosomes and they divide equally when cell divisions take place. But plants are very tolerant of having multiple sets and that's called polyploidy. Polyploid plants can be triploid, tetraploid, pentaploid, and up the numbers go! And it doesn't often badly affect the viability of the plant. They grow. They photosynthesize. They can produce fruits. But if they have odd numbers of chromosomes, they are stuffed. They can't have any babies at all. And that happens to the triploids and the pentaploids because you can't divide odd numbers evenly. If you want to multiply up that plant, you can do it by cloning or vegetative propagation. And that's an important thing for people setting out to grow large orchards of triploid fruit.Diana - So you can propagate plants which are gameteless so they make seedless fruit. And here's a little more on how it's done.Jennifer - When humans get involved, they try to manipulate things and they can do things like treat a plant with a chemical called 'colchicine' which disrupts the meiotic process. So when the plant is producing pollen grains and ovules, they will produce a gamete that has double the amount of chromosomes. So then when it is pollinated by the original plant that provides one copy of chromosomes, the result is a triploid plant. We talk about cloning being a really modern method, but actually, horticulturists have been using it for quite some time. Any time you're taking a cutting of a plant and rooting it using different plant hormones or simply sticking it in a glass of water, watching the roots grow and then planting that plant, that's cloning, also called 'vegetative propagation.' I actually found some information that when you talk about polyploidy in plants and it sounds like a really rare thing, but it's actually not that rare. Scientists think that anywhere from 30 to 70% of angiosperms from the plant kingdom are polyploidy and polyploidy plants tend to be larger. And so, maybe they're more competitive in nature and so that might be some advantage for that to be selected for in nature.Diana - Triploid plants can be reproduced using cloning and vegetative propagation as well as chemical mutagens like 'colchicine.' But many farms will grow the fertile parent plants nearby so that more seedless offspring can be produced later.

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