When you think about viruses, you might wonder how they infect, how they spread, and how they kill. These questions are of natural interest—you, after all, could play host to a grand variety of lethal viruses. But do remember: it’s not all about you.
A virus’ world contains not just potential hosts, but other viruses. It has competition. This simple fact is often ignored but it has profound implications. In a new study, Lisa Bono from the University of North Carolina has shown that competition between viruses can drive them to spill over into new hosts, imperilling creatures that they never used to infect.
Earlier this year, a 17-year-old French woman arrived at her ophthalmologist with pain and redness in her left eye. She had been using tap water to dilute the cleaning solution for her contact lenses, and even though they were meant to be replaced every month, she would wear them for three. As a result, the fluid in her contact lens case had become contaminated with three species of bacteria, an amoeba called Acanthamoeba polyphaga that can caused inflamed eyes.
It was carrying two species of bacteria, and a giant virus that no one had seen before—they called it Lentille virus. Inside that, they found a virophage—an virus that can only reproduce in cells infected by other viruses—which they called Sputnik 2. And in both Lentille virus and Sputnik 2, they found even smaller genetic parasites – tiny chunks of DNA that can hop around the genomes of the virus, and stow away inside the virophage. They called these transpovirons.
If flu viruses have favoured hook-up spots, then pig pens would be high on the list. Their airways contain molecules that both bird flu viruses and mammalian flu viruses can latch onto. This means that a wide range of flu strains can infect pigs, and if two viruses infect the same cell, they can shuffle their genes to create fresh combinations.
This process is called reassortment. In 2009, it created a strain of flu that leapt from pigs to humans, triggering a global pandemic. If we needed proof that pigs are “mixing vessels” for new and dangerous viruses, the pandemic was it.
Now, scientists have found a new strain of flu in Korean pigs that remphasises the threat. It’s an H1N2, subtly different to the H1N1 virus behind the recent pandemic. But it’s got all the makings of a serious problem. It can kill ferrets – the animal of choice for representing human flu infections. And it spreads through the air between them. I’ve written about this new strain for Nature News, so head over there for more details.
Image by US Dept of Agriculture
Jerka was the first. The 20-year-old polar bear was born in captivity, and had lived in Germany’s Wuppertal Zoo since the age of two. In the summer of 2010, she started suffering from epileptic seizures and eight days later, on the 16th of June, she finally passed away. Lars, a male bear who lived in the same enclosure, also became seriously ill. He was hooked up to an IV drip and treated with anti-seizure medicine. It took several weeks, but he eventually made a full recovery.
When the zookeepers dissected Jerka’s body, they found signs of inflammation in her brain. The pattern of damage pointed to a viral infection, but no one knew which virus was responsible. A team of scientists led by Alex Greenwood from the Leibniz-Institute for Zoo and Wildlife Research searched Jerka’s brain tissue for the genetic material of many possible viruses, from rabies to canine distemper virus. They found only one hit, and it looked a lot like EHV1 – a virus that infects horses.
HIV is an exceptional adversary. It is more diverse than any other virus, and it attacks the very immune cells that are meant to destroy it. If that wasn’t bad enough, it also has a stealth mode. The virus can smuggle its genes into those of long-lived white blood cells, and lie dormant for years. This “latent” form doesn’t cause disease, but it’s also invisible to the immune system and to anti-HIV drugs. This viral reservoir turns HIV infection into a life sentence.
When the virus awakens, it can trigger new bouts of infection – a risk that forces HIV patients to stay on treatments for life. It’s clear that if we’re going to cure HIV for good, we need some way of rousing these dormant viruses from their rest and eliminating them.
A team of US scientists led by David Margolis has found that vorinostat – a drug used to treat lymphoma – can do exactly that. It shocks HIV out of hiding. While other chemicals have disrupted dormant HIV within cells in a dish, this is the first time that any substance has done the same thing in actual people.
At this stage, Margolis’s study just proves the concept – it shows that disrupting HIV’s dormancy is possible, but not what happens afterwards. The idea is that the awakened viruses would either kill the cell, or alert the immune system to do the job. Drugs could then stop the fresh viruses from infecting healthy cells. If all the hidden viruses could be activated, it should be possible to completely drain the reservoir. For now, that’s still a very big if, but Margolis’s study is a step in the right direction.
HIV enters its dormant state by convincing our cells to hide its genes. It recruits an enzyme called histone deacetylase (HDAC), which ensures that its genes are tightly wrapped and cannot be activated. Vorinostat, however, is an HDAC inhibitor – it stops the enzyme from doing its job, and opens up the genes that it hides.
It had already proven its worth against HIV in the lab. Back in 2009, three groups of scientists (including Margolis’ team) showed that vorinostat could shock HIV out of cultured cells, producing detectable levels of viruses when they weren’t any before.
To see if the drug could do the same for patients, the team extracted white blood cells from 16 people with HIV, purified the “resting CD4 T-cells” that the virus hides in, and exposed them to vorinostat. Eleven of the patients showed higher levels of HIV RNA (the DNA-like molecule that encodes HIV’s genes) – a sign that the virus had woken up.
Eight of these patients agreed to take part in the next phase. Margolis gave them a low 200 milligram dose of vorinostat to check that they could tolerate it, followed by a higher 400 milligram dose a few weeks later. Within just six hours, he found that the level of viral RNA in their T-cells had gone up by almost 5 times.
These results are enough to raise a smile, if not an outright cheer. We still don’t know how extensively vorinostat can smoke HIV out of hiding, or what happens to the infected cells once this happens. At the doses used in the study, the amount of RNA might have gone up, but the number of actual viral particles in the patients’ blood did not. It’s unlikely that the drug made much of a dent on the reservoir of hidden viruses, so what dose should we use, and over what time?
Vorinostat’s actions were also very varied. It did nothing for 5 of the original 16 patients. For the 8 who actually got the drug, some produced 10 times as much viral RNA, while others had just 1.5 times more. And as you might expect, vorinostat comes with a host of side effects, and there are concerns that it could damage DNA. This study could be a jumping point for creating safer versions of the drug that are specifically designed to awaken latent HIV, but even then, you would still be trying to use potentially toxic drugs to cure a long-term disease that isn’t currently showing its face. The ethics of doing that aren’t clear.
Steven Deeks, an AIDS researcher from the University of California San Francisco, talks about these problems and more in an editorial that accompanies the new paper. But he also says that the importance of the study “cannot be overstated, as it provides a rationale for an entirely new approach to the management of HIV infection”.
Reference: Archin, Liberty, Kashuba, Choudhary, Kuruc, Crooks, Parker, Anderson, Kearney, Strain, Richman, Hudgens, Bosch, Coffin, Eron, Hazudas & Margolis. 2012. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature http://dx.doi.org/10.1038/nature11286
Image by Dr. A. Harrison; Dr. P. Feorino
More on HIV:
Since 2008, Australian chickens have been suffering from intense outbreaks of a disease called infectious laryngotracheitis (ILT). Their eyes become red and swollen, they cough and gasp for air, and they sometimes bleed from their noses. The survivors produce fewer eggs, leading to severe losses for farmers.
The disease is caused by a highly contagious virus called ILTV. It’s a herpesvirus, one of the group that causes herpes, chickenpox, and glandular fever in humans. It’s a problem for poultry the world over, but the recent outbreaks in New South Wales and Victoria have been unusually severe, killing up to 18 per cent of infected chickens. They also have an ironic origin – they’re the result of vaccines.
Chickens are often vaccinated against ILTV, using weakened versions of the virus. Now, Sang-Won Lee from the University of Melbourne has found that two such vaccines have merged together to create the live and virulent virus behind the recent outbreaks. The measures that were meant to protect the chickens have only made things worse. (Some of you may now be worrying or wondering if the same applies to human vaccines. You can skip straight to the end where I discuss this, but it’s worth knowing what actually happened first.)
I could write the entire genome of a flu virus in around 100 tweets. It is just 14,000 letters long; for comparison, our genome has over 3 billion letters. This tiny collection of genetic material is enough to kill millions of people. Even though it has been sequenced time and time again, there is still a lot we don’t know about it.
A new study beautifully illustrates the depths of our ignorance. Brett Jagger and Paul Digard from the University of Edinburgh have discovered an entirely new flu gene, hiding in plain sight among the 12 we knew about. It’s like someone took the text of Macbeth, put the spaces in different places, and got Hamlet.
This new gene, known as PA-X, affects how the virus’s host responds to the virus. Oddly, it seems to reduce the severity of infections. “This is indeed an exciting finding in the flu field,” says virologist Ron Fouchier. “How can we have missed it?” asks Wendy Barclay, a flu researcher from Imperial College London who has worked with Digard before. “It just emphasizes how compact these genomes are.”
There are few viruses more capable to grabbing headlines at the moment than H5N1, more commonly known as bird flu. It has certainly been discussed to death in the media over the last several months, after it emerged that two scientists had evolved mutant strains that can spread between ferrets. The first of those papers was published last month (I covered it for Nature News then) and the second comes out today (I’ve covered for Nature News now).
The fact that the papers are out is unlikely to quench the controversy about these mutant viruses. It’s a controversy that threatens to distract from a more important fact: we still know surprisingly little about H5N1. I’ve spent the last few weeks talking to flu researchers and it’s amazing how many basic questions about the virus we still have to answer.
Where is it, and how many people have been infected? How does it kill and, for that matter, why doesn’t it kill more people? Why did one particular lineage spread around the world, when other bird flu viruses have not? Given that the virus apparently evolve the ability to spread between mammals, as the controversial papers show, why hasn’t it already done so? And perhaps most importantly, what will it do in the future?
I’ve written a bigger story for Nature about these issues, corralled into five questions on H5N1. In a brilliant play on words, the story has been titled “Five Questions on H5N1”. Go have a look, if only to smile at the cute little cartoon viruses with their angry teeth and eyes.
Image by Martin Correns
HIV – the virus behind AIDS – is the most diverse of all viruses. Once it infects someone new, it mutates so rapidly that it can spawn a million genetically different strains in just a few months. This evolutionary onslaught overwhelms the host’s immune system, and creates big problems for any scientist trying to create a cure or a vaccine. By evolving so quickly, HIV turns itself into a million moving targets.
But when HIV jumps from one individual to another, something odd happens. The virus still mutates at a breakneck speed, but it does so 2 to 6 times more slowly than within any single person. Unexpectedly, the virus seems to evolve faster in a single host, than in a population.
There are three possible explanations for this puzzling trend, but Katrina Lythgoe and Christophe Fraser from Imperial College London think that only one is correct. They think that the ancestral strain – the one that kicked off someone’s infection – is more likely to spread to other people than its millions of descendants.
The progeny of the ancestral virus quickly evolve to avoid their host’s immune system and reproduce as rapidly as possible. But Lythgoe describes this as “short-sighted evolution”. As the viruses become better at growing within someone, they lose the ability to spread between people. “What is good for the virus in the short term (growing in a host) is not necessarily what is good in the long term (infecting the most people),” says Lythgoe.
Here’s the seventh piece from my new BBC column
For around 30 years we have lived under the spectre of HIV. In the early 1980s, the mysterious appearance of symptoms that would later be known as AIDS led to unprecedented efforts to unmask the cause. On 23 April 1984, Margaret Heckler, the US Secretary of Health and Human Services, told the world that scientists had identified the virus that was the probable cause of AIDS. She was correct. She also said that a vaccine would be “ready for testing in approximately two years.” She was wrong.
Despite 28 years of research, there is still no vaccine that provides effective protection against HIV, and in that time around 25 million people have died of HIV-related causes. To understand why creating a vaccine is so hard, you need to understand HIV. This is no ordinary virus. Scientists who study it speak of it with a mix of weary frustration and awed reverence.
The virus is the most diverse we know of. It mutates so rapidly that people might carry millions of different versions of it, just months after becoming infected. HIV’s constantly changing form makes it unlike any viral foe we have tried to thwart with a vaccine. “Almost every vaccine that’s been developed protects against a small number of strains,” says Gary Nabel, Director of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases (NIAID).