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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Drugs that work against each other could fight resistant germs

Using combinations of drugs that work poorly together could be the key to fighting strains of germs resistant to those same drugs. Drugs that block each other could actually switch off the evolutionary driving force that leads to drug-resistant bacteria.

When normal bacteria are exposed to a drug, those that gain a resistance gene also gain the huge and obvious advantage of invincibility. Bacteria are notoriously quick to seize upon such evolutionary advantages and resistant strains rapidly outgrow the normal ones.

Tuberculosis is developing increasingly resistant strains.Drug resistance poses an enormous potential threat to public health and their numbers are increasing. MRSA for example, has become a bit of a media darling in Britain’s scare-mongering tabloids.

More worryingly, researchers have recently discovered a strain of tuberculosis resistant to all the drugs used to treat the disease. New antibiotics are difficult to develop and bacteria are quick to evolve, so there is a very real danger of losing the medical arms race against these ‘super-bugs’.

Even combinations of drugs won’t do the trick, as resistant strains would still flourish at the expense of non-resistant ones. Antibiotic combos could even speed up the rise of super-bugs by providing a larger incentive for evolving resistance.

Clearly, fighting the rapidly evolving nature of bacteria is a dead end. So Remy Chait, Allison Craney and Roy Kishoni from Harvard Medical School used a different strategy – they changed the battle-ground so that non-resistant bacteria have the advantage.

Doxycycline works better against drug-resistant bacteria when given with a drug that it blocks!The trio looked at two strains of the common bacteria Escherichia coli – one that was normal, and another that was resistant to doxycycline.

Doxycycline is widely used to fight off a variety of bacterial invaders, but resistant E.coli use a specialised molecular pump to remove the drug. It can withstand 100 times more doxycycline than its normal counterparts.

First, the team hit the two strains with doxycycline and erythromycin, a combination of drugs that work particularly well together and enhance each other’s effects

The resistant strain was certainly more vulnerable to this double-whammy, but as expected, it always outperformed the normal bugs. With that advantage and enough time, it would inevitably evolve resistance to both drugs.

But Chait managed to remove this evolutionary impetus by combining doxycycline with a third drug, ciprofloxacin, a combination that would normally be useless. Doxycycline actually blocks the effects of ciprofloxacin, to the two drugs together are weaker than either alone.

To fight bacteria like MRSA, we need new strategiesPredictably, the resistant bug did what it had evolved to do – it pumped out doxycycline. But in doing so, it also unwittingly removed the block on ciprofloxacin, restoring this second drug to its full killing power.

The normal strain encountered no such problem. By leaving the drugs alone, it never faced the full effects of either, and out-competed their more heavily-pummelled resistant cousins.

Chait cautions that it’s too early to transfer his findings across to hospital beds. The experiment used non-lethal antibiotic concentrations in a very controlled environment. But they have certainly pointed other researchers down a new and interesting path.

Combinations of drugs that block each other have previously been dismissed by doctors because they would require higher doses. But Chait’s study suggests that they could be the key to controlling bacterial drug resistance.

We clearly can’t stop bacteria from evolving, but we can certainly steer the course of that evolution in our favour.

Reference: Chait, Craney & Kishony. 2007. Antibiotic interactions that select against resistance. Nature 446: 668-671.

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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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Of dogs and devils – the rise of contagious cancer

While human cancers cannot be transmitted from person to person, scientists have recently identified two types of contagious cancers in animals. In Tasmanian devils and domestic dogs, cancer cells have evolved into independent parasites, jumping from animal to animal like an infectious virus.

Cancer cells are, for all intents and purposes, immortal. Having broken free of the rules and strictures that govern other cells, they are free to grow and divide as they please. In a short space of time, a lone cancer cell can form a mass of identical clones – a tumour. Theoretically, cancers could exist indefinitely, but as always, there is a catch. Those that spread quickly and aggressively do so at the expense of their host, who usually ends up dying, taking the tumour with it.

But there is one way a cancer could escape this fate and carry on its selfish reproduction – by finding another host. It could become contagious.

In humans, cancers are definitely not contagious. You can’t catch cancer from someone who has it. At most, you can inherit a higher risk of developing cancer, because of faulty genes passed on from your parents. But recently, scientists have found some startling exceptions to this rule.

Even devils get cancerTasmanian devils are plagued by a contagious facial cancer

Earlier this year, Australian researchers Anne-Marie Pearse and Kate Swift found that a facial cancer plaguing the local Tasmanian devils (right) was caused by contagious cancers.

The condition, known as devil facial tumour disease, is spread when an infected devil bites another. The devils’ boisterous temperaments and their propensity for squabbling over carcasses mean that such bites are common.

Once infected, the animals develop grotesque tumours that stop them from feeding properly, and they usually die of starvation within six months. As a result, the cancer is decimating the already small population.

Going to the dogs

At University College London, Robin Weiss and Claudio Murgia have found another example of an infectious cancer – a disease called canine transmissible venereal tumour (CTVT), or Sticker’s sarcoma.

CTVT is transmitted through sex or close contact between infected dogs. It was first described 130 years ago by a German scientist called Novinski and its origins have been debated ever since. Some scientists suggested that it was caused by a virus, much like human papillomavirus (HPV) causes cervical cancer in humans today.

But in a study published this month, Weiss and Murgia have put these theories to rest. They and their colleagues analysed tumour samples from 40 dogs across five continents. All these samples shared identical and distinctive genetic markers that uninfected tissues from the same dogs did not.

The explanation was clear – these cancers had not developed in the usual way from the cells of the host animals. The cancer cells themselves were spreading from dog to dog.

Becoming contagious

CTVT evolved in an old Asian dog line, like the huskyThese rogue cells have become parasites in their own right, evolving from a single ancestor into a dynasty that has colonised the globe aboard canine vessels. How this process began is still a mystery, but Weiss’s analysis provides some hints as to where and when.

The original cancer cell must have developed in either a wolf or an old Asian dog lineage, such as a Husky (left). It evolved anywhere between 200 and 2500 years ago and may well have been around for even longer.

In fact, the CTVT cancer cell is very likely to be the oldest lineage of mammalian cells still in existence. The cells that Weiss is studying today are most probably direct clone descendants of the same cells that Novinski identified 130 years ago – genetically identical great-granddaughters of the original tumour.

To kill or not to kill

When that original cell gained independence, it became truly immortal, long outliving its original body and lasting for centuries. So far, we don’t know of any human cancer cells that have pulled off a similar trick. But Weiss feels that if they did, the best place to look for them would be in people with weaker immune systems including transplant patients and those with HIV.

His group have found evidence that evading the host’s immune defences is a key part of CTVT’s strategy for finding another dog to infect. The cells accomplish this by switching off some key immune system players – a group of genes collectively called dog leukocyte antigens (DLAs). They also secrete a protein called TGF-β1 that strongly blocks any immune responses.

But slipping past immune sentries would do the cells no good if the host died before infecting another dog. Infection requires sex, which may not happen for some time. So CTVT is a merciful parasite.

At the start of infection, it grows rapidly, but within 3-9 months, it regresses of its own accord. By never killing its carrier, the cells ensure that they can spread to as many new hosts as possible.

The Tasmanian devils are not so lucky. Their cancers are spread through biting, a more frequent event than sex, and as such, they can afford to be more aggressive. But the devils’ population is small and their genetic diversity is low. This combination may spell the end for both devils and cancer cells, unless some vaccine can be found.

 

Reference: Pearse & Swift. 2006. Nature 439: 549.
Murgia, Pritchard, Kim, Fassati & Weiss. 2006. Cell 126: 477-487.

 

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