Hepatitis C Virology

克里斯,我们本周是乔·格罗夫博士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.

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 ontheir 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 transmittedwithinthese 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. Howeverin 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.