Editing Ebola – how to tame one of the world’s deadliest viruses

Blogging on Peer-Reviewed ResearchIn a list of the most dangerous jobs in the world, ‘Ebola researcher’ must surely rank near the top. But if new research is anything to go by, it may soon fall several places. An international team of scientists have recently found a way to neuter the virus, making it easy to study without risking your life. The altered virus looks like Ebola and behaves like Ebola, but it can’t kill like Ebola. It should make studying the virus easier and most importantly, safer.

Ebola virusThe Ebolaviruses and their cousins, the closely related Marburg family, have a chilling and deserved reputation. In some outbreaks, 90% of those infected die from massive blood loss. There is no approved antiviral treatment. There is no vaccine. And given that it’s almost a rite du passage for infectious disease scientists to contract the contagion they study, working with Ebola is a delicate affair.

Maximum protection

Ebola research requires the highest level of safety possible – the “Biosafety Level-4” laboratory. The stand-alone facilities are designed to be easily sealed and impervious to animals and insects. All routes in and out, including all pipes and ventilation, are peppered with multiple airlocks, showers and rooms designed to prevent any chance of escaping viruses.

There are very few people who are qualified to work in such a prohibitive environment and those that do have to wear a Hazmat suit at all times and breathe from a self-contained oxygen supply. No wonder then that the majority of Ebola research doesn’t actually use live, infectious viruses.

Scientists must instead settle with isolated proteins, proteins shoved into other, less harmful viruses or even “virus-like particles”. But these artificial systems are different to the virus proper, and using them is like staring at a complex machine through a cobweb-covered keyhole. Peter Halfmann from the University of Wisconsin has found a way around this, opening the door for scientists to get a proper look at the virus.

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Flu viruses take the summer off to go travelling

It’s not just us who like to go travelling in the summer – flu viruses do it too. After a busy winter of infection, they turn into the gap-year students of the virus world. They travel round the world, meet new viruses, swap genetic material, and returning back, changed and unrecognisable (at least to our immune systems).

A close-up of a flu virus.The success of flu viruses hinges on their ability to rapidly fool our immune systems by changing the proteins that line their surface. Every year, they put on a new disguise that shield them from any immunity built up the year before, allowing them to constantly re-infect the same populations of people.

But when scientists looked for these fast evolutionary changes during the epidemic season (November to March in the northern hemisphere), they found surprisingly little. That suggests that the viruses evolve their new facades during their off-season and it could do so in two ways.

They could stay within the same host population in a dormant state, until changing climate stirs them into action. Alternatively, they could travel to other parts of the world, only to return the following year.

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Is a virus responsible for the disappearing bees?

A group of scientists have found that a virus – IAPV – may be responsible for Colony Collapse Disorder, the mysterious condition that’s emptying the hives of European and American beekeepers.

A bee sits on a readout of its own genetic material.In 2006, American and European beekeepers started noticing a strange and worrying trend – their bees were disappearing. Their hives, usually abuzz with activity, were emptying.

Like honeycombed Mary Celestes, there was no trace of the workers or their corpses either in or around the ghost hives, which still contained larvae and plentiful stores of food. It seemed that entire colonies of bees had apparently chosen not to be.

The cause of the aptly named ‘Colony Collapse Disorder’, or CCD, has been hotly debated over the last year. Fingers were pointed at a myriad of suspects including vampiric mites, pesticides, electromagnetic radiation, GM crops, climate change and poor beekeeping practices. And as usual, some people denied that there was a problem at all.

But a large team of US scientists led by Diana Cox-Foster and Ian Lipkin have used modern genomics to reveal the main villain in this entomological whodunnit – a virus called Israeli Acute Paralysis Virus or IAPV.

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Resistance to an extinct virus makes us more vulnerable to HIV

Immunity to viral infections sounds like a good thing, but it can come at a price. Millions of years ago, we evolved resistance to a virus that plagued other primates. Today, that virus is extinct, but our resistance to it may be making us more vulnerable to the present threat of HIV.

Many extinct viruses are not completely gone. Some members of a group called retroviruses insinuated themselves into our DNA and became a part of our genetic code.

Our resistance to the ancient PtERV1 may explain our vulnerability to HIV.Indeed, a large proportion of the genomes of all primates consists of the embedded remnants of ancient viruses. Looking at these remnants is like genetic archaeology, and it can tell us about infections both past and present.

Viral hitchhikers

When retroviruses (such as HIV, right) infect a cell, they insert their own DNA into their host’s genome, using it as a base of operations. From there, the virus can pop out again and make new copies of itself, re-infect its host or move on to new cells.

If it manages to infect an egg or sperm cell, the virus could pass onto the next generation. Hidden inside the embryo’s DNA, it becomes replicated trillions of times over and ends up in every single one of the new individual’s cells.

These hitchhikers are called ‘endogenous retroviruses’. While they could pop out at any time, they quickly gain mutations in their DNA that knocks out their ability to infect. Unable to move on, they become as much a part of the host’s DNA as its own genes.

In 2005, a group of scientists led by Evan Eichler compared endogenous retroviruses in different primates and found startling differences. In particular, chimps and gorillas have over a hundred copies of the virus PtERV1 (or Pan troglodytes endogenous retrovirus in full). Our DNA has none at all, and this is one of the largest differences between our genome and that of chimps.

Our ancestors shared a similar geographical range to the ancestors of these apes, and would have encountered the same viruses, including PtERV1. And yet, we were spared from infection, while the apes were not. Why?

Protecting against an ancient virus

HIV daughter particles - retroviruses like HIV can integrate into a host’s DNAShari Kaiser and colleagues from the University of Washington and the Fred Hutchinson Cancer Research Center believed that the answer lies in a protein called TRIM5α that defends us from retroviruses. It latches onto the outer coat of incoming viruses, and tells other proteins to dismantle or destroy them.

Other primates have their own versions of TRIM5α that protect against a different range of viruses, and the protein has evolved dramatically in different primate lineages. Kaiser believed that our version of TRIM5α protected us from PtERV1, while that of other apes did not. To test her idea, all she had to do was to resurrect a dead virus.

Obviously, PtERV1 is long extinct, but its remnants exist inside the genomes of chimps. Kaiser compared dozens of these remnants and by identifying common elements, she worked out the ancestral sequence of the virus.

She created a small part of PtERV1 and fused it with bits of a modern virus, MLV, to create a fully-functioning hybrid. To nullify any potential for spread beyond the lab, she crippled the virus so that it could infect once and only once.

The reconstructed virus successfully infected mammal cells in a lab, but not when human TRIM5α was around. The guardian protein demolished the virus’s infectivity, reducing it by more than 100 times. As Kaiser predicted, our genomes are free of PtERV1 because TRIM5α killed it before it could reach our DNA.

Resist one virus, succumb to another

TRIM5a provides antiviral protection that seesaws between different virus species.But this protection carries a price – it makes us vulnerable to HIV. Over the course of primate evolution, humans made an important change in the amino acid sequence of TRIM5α that allowed the protein to fight off PtERV1. When Kaiser changed the protein back to its original form, she found that it gained the ability to fight off HIV, but lost its resistance to PtERV1.

In fact, Kaiser found that no primate species has a version of TRIM5α capable of fighting off both viruses at the same time. We are resistant to ptERV1 and vulnerable to HIV, but chimps, gorillas, baboons and rhesus macaques show the reverse strengths and weaknesses.

When it comes to retrovirus immunity, there is no win-win situation. Having defeated one enemy, we have unwittingly made ourselves more vulnerable to another.

Reference: Kaiser, Malik & Emerman. 2007. Restriction of an extinct retrovirus by the human TRIM5a antiviral protein. Science 316:1756 – 1758.

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Related posts on viruses and virus evolution:
The upside of herpes – when one infection protects against another
Viruses evolve to be more infectious in a well-connected population
Round peg, square hole – why our bird flu drugs are a fluke

Related posts on new medical discoveries:
Drugs that work against each other could fight resistant germs
The secret of drug-resistant bubonic plague
Neutralising anthrax – moving closer to a cure

The upside of herpes – when one infection protects against another

When people say that every cloud has a silver lining, they probably aren’t thinking about herpes at the time. Herpes may be unpleasant, but the viruses that cause it and related diseases could have a bright side. In mice at least, they provide resistance against bacteria, including the bubonic plague.

Herpes is one of a number of itchy, blistering diseases, caused by the group of viruses aptly-named herpesviruses. Eight members infect humans and cause a range of illnesses including glandular fever, chickenpox, shingles, some rare types of cancer and, of course, herpes itself.

Herpesviruses cause a range of diseases, including cold sores, but could they protect against many more?Almost everyone gets infected by one of these eight during their childhood. But herpesviruses are for life, not just for Christmas. After you body fights off the initial infection, the virus retreats into a dormant phase known as ‘latency’.

It remains hidden and causes no symptoms, but has the potential to reactivate at a later date. In this way, herpesviruses can seem like life-long parasites, ensuring their own survival at the cost of their host’s future health. In extreme cases, latent viruses can lead to chronic inflammation, which in turn can cause autoimmune diseases, or some types of cancer.

Parasite or partner?

But there is a bright side too. Erik Barton and colleagues from Washington University Medical School found that once infected mice entered the latent stage, they were surprisingly resistant to certain types of bacteria. Unlike their vulnerable uninfected peers, they even managed to ward off the deadly plague bug, Yersinia pestis.

At least in mice, latent herpesviruses turn out to be paying tenants rather than free-loading squatters – bacterial resistance is their rent. The latent stage is crucial to the resistance effect, and Barton found that a mutant herpesvirus that infect but doesn’t set up shop provides no benefits to its host.

The viruses work their magic by putting the immune system on high alert. The effect is similar to a raising of the terror alert creating a heightened level of security where the body is prepared to fight off any further threats.

How it works

An activated macrophage hoovers up a bacterial meal.The viruses trigger the release of high levels of immune system chemicals called cytokines. These molecules – including interferon-gamma (IFN-g) and tumour necrosis factor alpha (TNF-a) – help to co-ordinate the defence against infections.

These chemicals activate macrophages – a type of white blood cell. These cellular assassins (above) engulf invading bacteria, and sentence them to death by digestion. And in mice latently infected by herpesviruses, they are activated in bulk.

This sequence is similar to the way the immune system normally protects us against multiple bacterial invaders. But in Barton’s experiments, the protection was set off by viruses instead, and lasted for much longer than normal.

From mice to humans

All well and good for the mice, but do these viruses benefit us too? Barton thinks so. In his study, two very different strains – murine gammaherpesvirus 68 (gHV68) and murine cytomegalovirus (MCMV) – had the same effect. He believes that providing bacterial resistance is a general property of all herpesviruses.

The HSV-1 virus - could it make us resistant to bacterial infection?There is certainly growing evidence to support his claims. If many people, the latent viruses reactivate regularly, but not strongly enough to cause major symptoms. In these cases, doctors have seen higher levels of cytokines and long-term activation of the immune system, just like Barton saw in his mice.

Barton even suggests that herpesvirus infection may play a role in protecting against allergies. According to the ‘hygeine hypothesis’, infections during childhood prime the immune system against future threats. By depriving children of these experiences, overly clean homes can lead to naïve immune systems that react disproportionately to harmless things like pollen. Allergies are the result.

It isn’t clear what role herpesviruses play in priming the immune system. But at least one study found that people who are infected with the Epstein-Barr herpesvirus (EBV) are less likely to show sensitive antibody reactions to allergens in their environment. Clearly, the subject is a rich vein for further research.

Almost everyone has had an encounter with a herpesvirus of some kind. They cause a wide range of diseases, but could they be protecting us from many more?

 

Reference: Barton, White, Cathelyn, Brett-McClellan, Engle, Diamond, Miller & Virgin IV. 2007. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447: 326-330.

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Viruses evolve to be more infectious in a well-connected population

We still don’t know enough about how viruses evolve to predict what would happen in a twenty-first century viral pandemic. New research in insects provides a clue – in a well-connected and well-travelled world, we would expect viruses to evolve to become more infectious.

If the media is to be believed, we are under the constant threat of a deadly viral pandemic. While bird flu certainly poses a very real threat if it evolves the ability to pass between humans, it is still difficult to say whether the doom-mongering is justified. At this stage, we don’t know enough about how viruses evolve over time to predict what would actually happen.

A flu virus - more infectious in our modern world?A virus, like any other carrier of genetic information, is only successfully if its offspring can infect new hosts. Its host must live to infect again, and the virus that kills its host prematurely signs its own evolutionary death sentence.

So over time, we might expect that the ideal virus would evolve to never kill any of its hosts – it would have zero ‘virulence’. It would also evolve to successfully infect every host it comes into contact with it – it would have a hundred per cent ‘infectivity’. In this way, a virus would turn any hosts it meets into long-lived virus factories.

But this expectation is based on a model with overly simple assumptions. It only holds true if the virus’s potential hosts are evenly-distributed and ignores questions of distance. In this artificial scenario, once one person in a population carries the virus, every other person has an equal chance of being infected.

Obviously, this is not the case – humans, for example, are concentrated in certain areas, be they villages or cities. And even highly infective viruses can only be spread to new hosts within easy reach.

In this more realistic world, highly infective viruses would soon infect every possible host in the local area, exhausting themselves of potential carriers. Strains that were less infective would then gain an advantage.

The larvae of the moth Plodia interpunctellaOn the face of it, this model makes sense, but testing it can be difficult. Needless to say, ethics committees might frown upon infecting people with viruses and constraining them to different locations to see what happens. Insects are another rmatter.

Michael Boots and Michael Mealor at the University of Sheffield have studied virus evolution using the larvae of the moth Plodia interpunctella, and the virus that infects it, PiGV. Plodia larvae can be easily reared in a solid and nutritious jelly, which they spend their young lives in, slowly eating their way around.

By changing the viscosity of the jelly, Boots and Mealor could slow down or speed up the moth’s movements, and they used this to study the effects of population movements on viral transmission.

In softer jellies, the highly mobile moths could spread over large areas, and the viruses they carry have a wide choice of future hosts. But in harder jellies, moths are more likely to bump into the same individual again and again, and local transmission becomes more important.

After forty weeks and eight generations, Boots and Mealor compared the viruses carried by moths living in hard and soft jellies. They found that those infecting the concentrated hard-jelly larvae were three times less infective than those living from the free-roaming soft-jelly moths.

This provides direct evidence in populations with low movement rates, evolution drives viruses to become less infective. Even very subtle changes in a host population led to strong differences in viral characteristics.

Air travel leads to a well-connected world, and possible, more infectious viruses. Imagine then, what large changes would lead to. Our world is becoming more and more connected. Air travel is easy and cheap while foreign holidays are becoming par for the course. As our populations mix and local interactions become less important, we would be wise to expect viruses to react accordingly.

Boots and Mealor’s results suggest that globalisation will lead to the rise of even more infective strains of viruses and other parasites, and larger epidemics.

Boots and Mealor. 2006. Local interactions select for lower pathogen infectivity. PNAS 315: 1284-1286.

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Round peg, square hole – why our bird flu drugs are a fluke

The world’s nations are stockpiling two drugs, Tamiflu and Relenza, to counter the threat of a bird flu pandemic. These drugs work by blocking a key protein that allows the virus to spread. But a new report had revealed the structure of this protein and shown that these drugs only work through a fortunate fluke.

H5N1 bird flu can be carried by poultry. The threat of bird flu is looming large in the minds of the public, scientists and politicians alike. So far, 143 people have died of the disease across 9 countries. But the real worry is that that the virus could mutate into a form that passes from person to person, triggering a pandemic that could kill millions.

The pandemic threat has started a race to produce drugs that can quickly halt the progress of the virus in infected patients, reducing the chances of mutation and transmission. Two drugs have been created – oseltamivir, better known as Tamiflu, and zanamivir, also known as Relenza. But worrying reports of resistance to these drugs are starting to emerge and there is a growing need for newer and better weapons. And as always, to find the ideal weapon, you must first know your enemy.

There are many types of bird flu, but the strain that has us concerned is called H5N1. The N stands for neuraminidase, a protein that allows newborn viruses inside the host to break free and spread to new cells (see diagram below). There are nine types of neuraminidase that fall into two distinct sub-groups; N1 belongs to group 1.

Tamiflu and Relenza were designed to block the action of neuraminidase by attaching to their ‘active site’ – the business end of the protein, and is the key to its activities. Blocking the site stops the spread of the virus, and contains the infection.

Even though these drugs are used to fight H5N1, they were designed to block the active sites of group-2 neuraminidases. Scientists had found that the active sites of both group-1 and group-2 proteins shared very similar amino acid sequences, and therefore assumed that they had the same structure. The correctly-shaped drugs would work against both groups.

The structure of the neuraminidase proteinBut Rupert Russell at the MRC National Institute for Medical Research has found that we were wrong. His team deciphered the structures of the group-1 neuraminidases, N1, N4 and N8 and found that their active sites are very different to those of their group-2 counterparts.

Because of this difference, it seems very strange that our drugs should work at all. At it happens, we have been very lucky. In a remarkable fluke, Tamiflu causes the active sites of the group-1 proteins to change shape to match those of the group-2 proteins it was manufactured against. The effect is like trying to fit a round peg into a square hole, but ramming it in so that it clogs up the hole anyway.

With the real structure of the N1 active site in hand, we now know the true face of the enemy. Scientists can begin designing a new wave of drugs that will be even more effective against the looming bird flu threat.

But the real moral of this story is that we must not be careless in designing new drugs. The mistake was in assuming that similar active site sequences implies similar active sites. But Russell’s experiments have shown that even small changes other parts of the protein can cause the active sites to take on very different shapes, reducing the effectiveness of any counter-measures. We have been very lucky with Tamiflu, and we cannot afford to rely on good fortune again.

 

Russell, Haire, Stevens, Collins, Lin, Blackburn, Hay, Gamblin & Skehel. 2006. Nature 443: 45-49.