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
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:
WARNING: The conclusions in this paper have been criticised in recent years and many groups have failed to replicate the findings. There is also evidence that XMRV is a recent creation of lab experiments. The journal Science has since asked the authors to retract the paper.
Chronic fatigue syndrome (CFS) is a disease that afflicts people with extreme and debilitating tiredness that lasts for many years and isn’t relieved by rest. Some estimates suggest that it affects up to 1% of the world’s population. We don’t know what causes it. Prostate cancer is one of the most common cancers in the world and kills around 221,000 people every year. Its causes too are largely unknown. What do these two diseases have in common? They have both been recently linked to a virus called XMRV (or xenotropic MulV-related virus in full). This doesn’t mean that you can ‘catch’ either prostate cancer or CFS. We don’t even know if XMRV actually causes either disease – it could just be that people with weakened immune systems (such as cancer patients or those with CFS) are more easily infected by the virus. For the moment, it’s a fascinating link but one that raises more questions than it answers. XMRV was first discovered in prostate cancer patients in 2006, and a recent study found XMRV genes in 6% of prostate cancers compared to just 2% of healthy prostates. The virus’s proteins were more starkly linked to cancerous prostates and overall, these tissues were 5 times more likely to carry the virus than their healthy counterparts. Now Vincent Lombardi and Francis Ruscetti have discovered that the XMRV is also over 50 times more common in CFS patients than in the general healthy population.
Since late 2006, honeybees in Europe and North America have been mysteriously disappearing. Once abuzz with activity, hives suddenly turned into honeycombed Marie Celestes. They still had plentiful supplies of honey, pollen and youngsters but the adult workers vanished with no traces of their bodies. The phenomenon has been dubbed colony collapse disorder (CCD). In the first winter when it struck, US hive populations crashed by 23% and in the next winter, they fell again by a further 36%.
Eager to avert the economic catastrophe that a bee-less world, scientists have been trying to find the cause behind the collapse. Amid wackier explanations like mobile phone radiation and GM crops, the leading theories include sensitivity to pesticides, attacks by the vampiric Varroa mite or a parasitic fungus called Nosema, infections by various viruses, or combinations of these threats.
In 2007, US scientists thought they had revealed the main villain in the piece, by showing that the an imported virus – Israeli acute paralysis virus (IAPV)- was strongly linked to empty hives. But since then, another group showed that IAPV arrived in the US many years before the first signs of CCD were reported. Other related viruses have also been linked to CCD hives, including Kashmir bee virus (KBV) and deformed wing virus (DWV).
To pare down these potential culprits, Reed Johnson from the University of Illinois compared the genetic activity of bees from over 120 colonies, including some affected by CCD and healthy ones that were sampled before the vanishing began. He looked at their digestive systems – one of the most places where infections and environmental toxins would start wreaking havoc.
The analysis didn’t offer any simple answers, but Johnson found some evidence to suggest that CCD bees have problems with producing proteins. In animal cells, proteins are manufactured in molecular factories called ribosomes. These factories assemble proteins by translating instructions encoded within molecules of RNA. Ribosomes themselves are partially built form a special type of RNA known as rRNA. And when Johnson looked at the guts of CCD bees, he found unusually high levels of fragmented rRNA.
This article is reposted from the old WordPress incarnation of Not Exactly Rocket Science. There’s been more work on CCD since, but I’m reposting this mainly because of some interesting follow-up research that will I will post about tomorrow.
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. There were no traces 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 a new villain in this entomological whodunnit – a virus called Israeli Acute Paralysis Virus or IAPV. By and large, the team found that where there was IAPV, there was CCD. The virus and the affliction were so stongly connected that Cox-Foster and Lipkin estimated that a hive infected with IAPV had a 96% chance of suffering from CCD. Once infected, the chances of a colony collapsing shot up by 65 times.
Viruses and bacteria often act as parasites, infecting a host, reproducing at its expense and causing disease and death. But not always – sometimes, their infections are positively beneficial and on rare occasions, they can actually defend their hosts from parasitism rather than playing the role themselves.
In the body of one species of aphid, a bacterium and a virus have formed a unlikely partnership to defend their host from a lethal wasp called Aphidius ervi. The wasp turns aphids into living larders for its larvae, laying eggs inside unfortunate animals that are eventually eaten from the inside out. But the pea aphid (Acyrthosiphon pisum) has a defence – some individuals are infected by guardian bacteria (Hamiltonella defensa) that save their host by somehow killing the developing wasp larvae.
H.defensa can be passed down from mother to daughter or even sexually transmitted. Infection rates go up dramatically when aphids are threatened by parasitic wasps. But not all strains are the same; some provide substantially more protection than others and Kerry Oliver from the University of Georgia has found out why.
H.defensa‘s is only defensive when it itself is infected by a virus – a bacteriophage called APSE (or “A.pisum secondary endosymbiont” in full). APSE produces toxins that are suspected to target the tissues of animals, such as those of invading wasp grubs. The phage infects the bacteria, which in turn infect the aphids – it’s this initial step that protects against the wasps.
As the world is now painfully aware, pigs can act as reservoirs for viruses that have the potential to jump into humans, triggering mass epidemics. Influenza is one such virus, but a group of Texan scientists have found another example in domestic Philippine pigs, and its one that’s simultaneously more and less worrying – ebola.
There are five species of ebolaviruses and among them, only one – the so-called Reston ebolavirus – doesn’t cause disease in humans. By fortuitous coincidence, this is also the species that Roger Barrette and colleagues have found among Philippine pigs and even among a few pig farmers.
The team were called in last July by the Philippine Department of Agriculture to identify a mystery illness that was sweeping across the country’s pigs, infecting their lungs and airways and causing miscarriages. Barrette’s group collected tissue samples from five groups of pigs throughout the island and through a battery of tests, they gradually ruled out their list of potential candidates – foot-and-mouth disease, African swine fever, and others.
The first positive hit was an infection known as blue ear disease, or to give it its formal name – porcine reproductive and respiratory syndrome virus (PRRSV). It was already the primary suspect for the pig illness, and the Philippine strain was genetically similar to one that was sweeping through China at the time. It seemed like the mystery was solved. But not so – when Barrette incubated an infected lymph node with monkey cells that are immune to PRRSV, the cells still started dying. There was another virus.
To identify it, Barrette used a powerful tool called a “panviral microarray” – a small slide that contains the genetic signatures of tens of thousands of viruses, neatly arranged in a grid. Similar tools have already proved their worth in viral detective work – the closely related Virochip was used to identify the SARS virus in 2002. This time, the technique brought up a strong hit for Reston ebola.
In the time since the words “swine flu” first dominated the headlines, a group of scientists from three continents have been working to understand the origins of the new virus and to chart its evolutionary course. Today, they have published their timely results just as the World Health Organisation finally moved to phase six in its six-tier system, confirming what most of us already suspected – the world is facing the first global flu pandemic of the 21st century.
The team, led by Gavin Smith at the University of Hong Kong, compared over 800 viral genomes representing a broad spectrum of influenza A diversity. The viral menagerie included two samples of the current pandemic strain (the virus formerly known as swine flu and now referred to as swine-origin influenza virus (S-OIV)). Also in the mix were 15 newly sequenced swine strains from Hong Kong, 100 older swine strains, 411 from birds and 285 from humans.
The team used these genomes to build a viral family tree that shows the relationships between the strains and dates their origins. They found that S-OIV was borne of several viruses that circulate in pigs, with contributions from avian and human strains. The virus made the leap to humans several months before we twigged to its presence. It was spreading right under our noses, undetected because of our lack of surveillance of flu viruses in pigs.
This beautiful diagram (enlarge it) charts the origins of the current outbreak. Each set of eight lines and arrows represents the genome of the influenza virus, which consists of eight separate strands of RNA. The bold dots on the far right represent the strain that currently troubles us. Trace back the lines of its ancestry and you can see that every one of its eight genetic segments comes from a lineage of flu that had firmly established itself in pigs for at least a decade before the current outbreak. Go back further and you can see that some of the segments have their origins in human H3N2 subtypes and bird H1N1 subtypes in the 70s and 80s.
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 and, of course, herpes itself.
Almost everyone gets infected by one of these eight during their childhood. But herpesviruses are for life, not just for Christmas. After your 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.
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.
This is the eighth of eight posts on evolutionary research to celebrate Darwin’s bicentennial.
In Virginia, USA, sits a facility called the American Type Culture Collection. Within its four walls lie hundreds of freezers containing a variety of frozen biological samples and among these, are 99 strains of the common cold. These 99 samples represent all the known strains of the human rhinoviruses that cause colds. And all of their genomes have just been laid bare.
Ann Palmenberg from the University of Wisconsin and David Spiro from the J. Craig Venter Institute have cracked the genomes of all 99 strains, and used them to build a family tree that shows the relationships between them. Already, it has started to plug the holes in our understanding of this most common of infections. It reveals how different strains are related and how new strains evolve. It tells us which features are shared by all strains and which are the more unique traits that making rhinoviruses such slippery targets.
This extra knowledge may go some way to remedying the slightly baffling situation we find ourselves in, where all the vaunted progress of modern medicine has failed to produce a single approved treatment for an infection that most of us get at least twice a year.
The 99 historical strains of human rhinovirus fall into two separate species – HRV-A and HRV-B. More recently, a possible third species – HRV-C – has been identified in patients hospitalised with severe, flu-like illnesses. To build their family tree, Palmenberg and Spiro analysed the complete genomes of all 99 strains from the Virginia facility, seven samples of HRV-C, and 10 fresh samples collected from patients just a few years ago.