HIV is a very sneaky virus that has developed many strategies of evading the immune system. One of the strategies is direct transmission of viral particles from cell to cell. What other viruses normally do, is they infect a cell, use it to multiply themselves in the thousands and make the cell release the new viral particles ready to infect further cells. But cells infected by HIV also do something else. They create tiny channels by which they connect their content with the content of another cell. And HIV uses these channels like a motorway to quickly travel to a new cell and establish a new replication centre.
In a recently published study (1), scientists hypothesised that this highway route of transmission might not only be faster and more efficient in infecting new cells, but also increase the chances of the virus escaping the action of anti-retroviral drugs. Here’s what their theoretical idea was.
If an infected cell releases viruses to the environment, the new virus, before infecting the next cell, drifts around in the solution randomly, as HIV has no mechanism to home onto target cells. It’s a little bit like standing with your mouth open when it’s snowing: even though there are thousands and thousands of snowflakes around, only a small number will make it on your tongue. Let’s call this way a drifting virus infection. However, imagine there was a tube that you put in your mouth that has a large funnel on the other side. Hundreds of snowflakes would find it much easier to travel directly through the tune into your mouth. Let’s call this funnelled infection. Now, let’s change the analogy and think of the virus as wasps invading your house and travelling straight onto the doughnuts on your kitchen table, and your anti-wasp spray will be the anti-retroviral drug. When you get the odd wasp every now and then (drifting infection), you can easily fend them off with your spray. But when you get hundreds of them barging through your window in an instant (funnelled infection), chances are, you will miss a few and they will reach the doughnuts. In the viral terms, it means escaping the anti-retroviral drugs and establishing an replication centre in a new cell. So this was the scientists’ theory, but how did they test it? Quite simply. They took some cells and mixed them with a solution of the virus, and either mixed in some drugs or not. As expected, many cells got successfully infected in the absence of the drug, while in its presence, very little did. For the second part of the experiment, they mixed some cells which were already infected by the virus and were red with some uninfected cell, which were green. And again, they did it in the presence or absence of the drug. After some time they removed all the red cells, and counted how many of the green ones were infected. And consistently with their theory – even though the drug decreased the number of green cells getting infected, this reduction was nowhere near as successful as that observed in the first part of the experiment. The wasps flew in in their hundreds and often managed to escape the spray.
AIDS is one of the worst pandemics to have ever affected the world. There is no cure, and the development of a successful vaccine is still in infant stages. Currently, the only thing that can be done is to use anti-retroviral therapy to control the virus and minimise the damage it does to patient’s body. The research I mentioned here can be seen as both bad news and good news. Bad news, because it shows the weakness of the current anti-retroviral therapy. Good news, because it showed how important this alternative way of virus transmission is. Now that we realise it, we can try to develop new drugs, which will close the connections between the cells. Or, using our metaphor, close the window and not let any wasps in. There’s a new challenge, a new hope.
1. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy
Tuesday 23 August 2011
Wednesday 17 August 2011
Protein crowding can harm and help
Some time ago, I wrote about how mislocalised proteins get binned immediately. Otherwise they might form dangerous clusters, such as those that cause the human form of mad cow disease. It turns out that this process – protein aggregation – might actually play an important role in our bodies and help protect us against viruses.
Faulty prion proteins are deadly not because their localisation and shape is incorrect, but because they cause deformation of other proteins which were normal to that point. Then, the newly distorted protein deforms another one and so on. This chain reaction on one hand partially depletes the cell of normally shaped and functional proteins and on the other, causes aggregation of the misfolded ones, which you might think of as a big pile of sticky rubbish. When a neuron cell is overwhelmed by such a pile, it can no longer function normally and decides to die. Such a decision, a cell suicide, by scientists called ‘apoptosis’, is nothing unusual and happens to many cells in every healthy person’s body. Normally, a suicide cell partially digests itself from the inside and the “corpse” is removed by other cells. But the problem with a prion aggregates from a dead cell is that they are very resistant to digestion. They persist and can come in contact with normal proteins on surrounding cells, causing them to misfold. This process is similar to a viral infection: a virus, after killing one cell, in which it copied itself thousands of times – infects further cells. And similarly, a misfolded prion protein – after forcing other proteins to misfold and killing the cell it originated in – moves on to other cells and causes more damage.
All of the above makes it seem like the progressive aggregation of proteins is something dangerous and deadly. But scientists in Texas found that there is another protein that behaves in a very prion-like way, but actually does it to protect us (1). The protein is called MAVS and it was known for quite a while that it responds to viral infections: when a virus enters a cell, the MAVS protein is able to pick it up and instruct the cell to activate an anti-viral programme. Fajian Hou and colleagues showed that what viral infection actually does, is aggregation of the MAVS protein, and only in this clustered form can it start the virus defence. They also found that even MAVS aggregates made synthetically (and not by viral infection) are able to activate the anti-viral programme. And these aggregates, just like prions, after enzymatic digestion don’t get destroyed and are still functional. Another similarity to prions came from the observation that pre-made MAVS clusters can enforce aggregation of natural MAVS proteins. And all this happens to help our cells fight the viral invaders.
From all of the above it appears that MAVS can very much behave like a prion protein – it aggregates, it doesn’t get digested easily and it can make other MAVS proteins aggregate too. But instead of making us worse – this actually helps to make us better. It is not clear however, what happens next. Since the aggregates are so resistant to digestion – how are they cleared? Is there another yet-unknown enzyme that actually can digest or untangle them? Do they de-aggregate spontaneously? Hopefully, one day these questions will find answers and the answers will help fight diseases caused by the evil prions.
1. MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response
Faulty prion proteins are deadly not because their localisation and shape is incorrect, but because they cause deformation of other proteins which were normal to that point. Then, the newly distorted protein deforms another one and so on. This chain reaction on one hand partially depletes the cell of normally shaped and functional proteins and on the other, causes aggregation of the misfolded ones, which you might think of as a big pile of sticky rubbish. When a neuron cell is overwhelmed by such a pile, it can no longer function normally and decides to die. Such a decision, a cell suicide, by scientists called ‘apoptosis’, is nothing unusual and happens to many cells in every healthy person’s body. Normally, a suicide cell partially digests itself from the inside and the “corpse” is removed by other cells. But the problem with a prion aggregates from a dead cell is that they are very resistant to digestion. They persist and can come in contact with normal proteins on surrounding cells, causing them to misfold. This process is similar to a viral infection: a virus, after killing one cell, in which it copied itself thousands of times – infects further cells. And similarly, a misfolded prion protein – after forcing other proteins to misfold and killing the cell it originated in – moves on to other cells and causes more damage.
All of the above makes it seem like the progressive aggregation of proteins is something dangerous and deadly. But scientists in Texas found that there is another protein that behaves in a very prion-like way, but actually does it to protect us (1). The protein is called MAVS and it was known for quite a while that it responds to viral infections: when a virus enters a cell, the MAVS protein is able to pick it up and instruct the cell to activate an anti-viral programme. Fajian Hou and colleagues showed that what viral infection actually does, is aggregation of the MAVS protein, and only in this clustered form can it start the virus defence. They also found that even MAVS aggregates made synthetically (and not by viral infection) are able to activate the anti-viral programme. And these aggregates, just like prions, after enzymatic digestion don’t get destroyed and are still functional. Another similarity to prions came from the observation that pre-made MAVS clusters can enforce aggregation of natural MAVS proteins. And all this happens to help our cells fight the viral invaders.
From all of the above it appears that MAVS can very much behave like a prion protein – it aggregates, it doesn’t get digested easily and it can make other MAVS proteins aggregate too. But instead of making us worse – this actually helps to make us better. It is not clear however, what happens next. Since the aggregates are so resistant to digestion – how are they cleared? Is there another yet-unknown enzyme that actually can digest or untangle them? Do they de-aggregate spontaneously? Hopefully, one day these questions will find answers and the answers will help fight diseases caused by the evil prions.
1. MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response
Wednesday 3 August 2011
New hope for after-stroke treatment
But the message is not crystal-clear
Researchers from Stanford, California, have found that a protein well-known to be a part of our eyes might provide protection after stroke. The protein is called crystallin and is called so because it was discovered as a protein that supports our eye lens structure and is responsible for its optical properties. It was later found to be produced by other tissues of the body including many kinds of brain cells. Ahmet Arac and colleagues set out to investigate if the protein might have any function in the aftermath of a brain stroke.
When mice suffered stroke, the researchers discovered that animals that were not able to produce crystallin, showed larger area of brain injury and the stroke itself affected their motor functions to a much greater extent. When they looked closer at the lesions, they found there was much more inflammation going on in the animals without crystallin. Even though inflammation is there to fight damage, when excessive, can cause even more of it. To make sure that it is crystallin that makes the difference, the scientists went on to inject it into the mice that couldn’t produce it themselves. And as expected, this procedure made the brain lesions size comparable to that seen in mice which can readily produce their own crystallin. But then they thought – that’s not actually a real-life situation, because all humans produce crystallin, so we could never use it to help people who don’t. So they decided to check if they will see any difference after injecting crystallin to mice that can produce their own. And indeed – when the protein was given to these animals after the stroke their lesion area was much smaller than when they received no treatment. And importantly, this effect was apparent even when they waited with the injections until 12 hours after the injury. Now that seems to be more applicable in real-life situations, especially when something stands in the way of immediate treatment of a stroke victim. And apart from experiments in mice, the researchers also asked whether crystallin might be important in human strokes. They tested the blood of several patients who have suffered stroke and discovered that indeed the protein levels are higher than in healthy people, which might suggest that human body after stroke also uses that protein to minimise the damage caused.
So is this discovery a new hope for stroke patients? Might very well be. The research quite convincingly shows that crystallin plays an important part in minimising the damage done to the brain following a stroke, by alleviating the severity of the inflammation. It even shows that injecting crystallin as a post-stroke intervention can do the trick. But what I found missing from these studies, is looking at how the animals did in terms of motor functions after they were given the protein, as the authors did not show that. Obviously having less inflammation in your brain is an encouraging result, but is it still any good if there is no difference in the damage caused? Hopefully they will address this issue soon and a new treatment for stroke patients might soon be under way.
Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation
Researchers from Stanford, California, have found that a protein well-known to be a part of our eyes might provide protection after stroke. The protein is called crystallin and is called so because it was discovered as a protein that supports our eye lens structure and is responsible for its optical properties. It was later found to be produced by other tissues of the body including many kinds of brain cells. Ahmet Arac and colleagues set out to investigate if the protein might have any function in the aftermath of a brain stroke.
When mice suffered stroke, the researchers discovered that animals that were not able to produce crystallin, showed larger area of brain injury and the stroke itself affected their motor functions to a much greater extent. When they looked closer at the lesions, they found there was much more inflammation going on in the animals without crystallin. Even though inflammation is there to fight damage, when excessive, can cause even more of it. To make sure that it is crystallin that makes the difference, the scientists went on to inject it into the mice that couldn’t produce it themselves. And as expected, this procedure made the brain lesions size comparable to that seen in mice which can readily produce their own crystallin. But then they thought – that’s not actually a real-life situation, because all humans produce crystallin, so we could never use it to help people who don’t. So they decided to check if they will see any difference after injecting crystallin to mice that can produce their own. And indeed – when the protein was given to these animals after the stroke their lesion area was much smaller than when they received no treatment. And importantly, this effect was apparent even when they waited with the injections until 12 hours after the injury. Now that seems to be more applicable in real-life situations, especially when something stands in the way of immediate treatment of a stroke victim. And apart from experiments in mice, the researchers also asked whether crystallin might be important in human strokes. They tested the blood of several patients who have suffered stroke and discovered that indeed the protein levels are higher than in healthy people, which might suggest that human body after stroke also uses that protein to minimise the damage caused.
So is this discovery a new hope for stroke patients? Might very well be. The research quite convincingly shows that crystallin plays an important part in minimising the damage done to the brain following a stroke, by alleviating the severity of the inflammation. It even shows that injecting crystallin as a post-stroke intervention can do the trick. But what I found missing from these studies, is looking at how the animals did in terms of motor functions after they were given the protein, as the authors did not show that. Obviously having less inflammation in your brain is an encouraging result, but is it still any good if there is no difference in the damage caused? Hopefully they will address this issue soon and a new treatment for stroke patients might soon be under way.
Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation
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