Hosting a killer
In light of recent virus outbreaks, Ian Jones provides an overview of the agents we tolerate throughout life yet which cause constant concern.
- Viruses strike a balance between replication and disease severity
- Once adapted for specific cells, viruses can rarely jump the species barrier successfully
- Drugs working on viral mutatability could offer a general treatment, as most virus mutations are a dead-end
Were it not for the fact that viruses cause diseases for which, in many instances, we have no cure, they might well vie with the current Spirit Mars rover pictures for favourite poster art. The symmetry of viruses, their contours, their intricate surface features which hint at a biological purpose sum to a miracle of micro engineering. Nature's nanobots are precision molecular machines whose sole job in life is to reproduce without end. The 'grey goo' as described by Prince Charles in the UK is already with us; the corpse of a caterpillar dead from an insect virus infection is nothing more than a bag of virus particles waiting for release into the environment. Human victims of the more dramatic of virus infections, haemorrhagic viruses such as Ebola, are, at the end, little more.
Viruses have been us with since early in recorded history. When the sarcophagus of Rameses V (12th century BC) was opened and the mummy unwrapped, his cheeks, still well enough preserved to show skin features, showed pockmarks typical of those associated with smallpox infection. An early victim of the disease that was to remain a scourge of humanity until Edward Jenner's vaccination of the gardener's son James Phipps in 1796. Pictorial evidence of paralytic polio, a virus very different from smallpox, is also known from around 3000 years ago.
These examples are notable as very few viruses leave a surviving marker following infection. The normal response to virus infection, antibodies in the blood, does not survive the host and so evidence of our most common viral infections is only handed down through written descriptions of symptoms. Hippocrates' description of hepatitis around 500 BC is almost certainly the result of infection with one of the many viruses now known to cause the disease.
Chemically, viruses are a mix of polymers. One form of nucleic acid, DNA or RNA, wrapped in a polypeptide chain. In some viruses there is an additional lipid layer and bigger, more complicated viruses, smallpox is one, have a far more complex make-up but the basic principle of nucleic acid-in-a-coat holds true throughout the viral world. Their simple chemistry is the reason they are often thought of as being on the edge of life.
In 1935, Wendell Stanley obtained a simple plant virus in crystalline form defining, as he did so, the basic chemicals of life and causing consternation in the process (can chemicals be 'alive'?). Their life, in fact, is potential as viruses are close to the most bare elements of evolution. Their genomes encode the minimum set of genes to enable replication of themselves and transmission to another host and they do this by parasitising more complex organisms. Inside a host cell viruses encode one simple loud message, 'make more virus', and the virus replication cycle, which may include a number of distinct biochemical steps, is almost wholly dedicated to this single task. The result to us, or to any other organism that becomes infected, is the distress of infection, but from the virus point of view it is the natural outcome of landing on fertile ground. As a strategy for gene survival, it works spectacularly well; every living thing on the planet has a virus that infects it, as diverse in themselves as the hosts they invade. Disease is simply the consequence of the process. It is sometimes innocuous, the common cold is distressing but rarely fatal, and sometimes severe, the outcome of HIV infection is only a matter of time. But it is a sideshow to the main event. Virus infection is wholly concerned with making more virus. One virus in, thousands of viruses out - job well done.
Some viruses have gone further still. The sequencing of whole animal genomes has led to the discovery that the genetic remnants of many viruses lie scattered throughout our genes. At earlier times in evolution, these viruses infected successfully but then integrated into the host genetic material. They have exchanged their ability to multiply extensively, but with the uncertainty of having to find a new host, for a steady life being quietly passed on within the genome of the host along with procreation; a daredevil turned accountant.
Those viruses with the slash and burn lifestyle we associate with severe infectious disease are only part of the virus world. Indeed, it is a moot point among virologists which of these lifestyles is the driving force for virus evolution. The available evidence suggests that viruses tend to the happy medium where virus replication and disease severity meet in the middle. When myxomatosis, a mild rabbit pox virus imported from the US to control the rabbit population in Australia, was first released in 1950 the results were devastating for the rabbit population. They died in their hordes. But within three years the toll was lighter, rabbit and virus had evolved so that the virus replicated enough to transmit in the long term but the rabbits also survived the infection. Human cytomegalovirus is just an extreme example of the happy medium trend having struck the trading deal with the human host many millennia ago.
Which brings us to the real challenges of modern virology. If, in time, virus and host populations survive, why should we worry about virus infections at all? There are three reasons, one overarching and two secondary. The major concern is the time frame involved in virus adaptation. A choppy sea precedes a calm and waves of virus infection are a real and persistent recurrence throughout history.
Orf, a sheep poxvirus that causes sores around the mouth of sheep and goats, is an occupational hazard for sheep handlers where it causes local lesions on the hand. But it goes no further. The virus, adapted as it is for sheep cells, cannot fully get going in human cells and the infection fizzles out. The cases of zoonotic infections (from animal to man) cause such concern because if the virus infection does take hold then it does so within a virgin population. No existing immunity to the virus will exist in the new species and virus replication can proceed unchecked with devastating results.
The 1918 influenza pandemic is thought to have originated from birds but the virus had the good fortune (from the virus point of view) to be equipped with mutations that enabled efficient entry into, and replication in, human cells. Between 20 million and 40 million people died; some pacific islands lost half of their adult population. That threat is the reason why the avian flu outbreak in southeast Asia this year was alarming. All the necessary ingredients were present. The H5N1 strain of influenza was known to be capable of devastating disease. Poultry farmers would report a poultry house late at night full of squawking and scratching birds which, next morning, was deathly silent. All the birds had died within a single night. And a dense human population surrounded the avian outbreak. The mix had the inevitable consequence and the virus did transmit to cause 22 deaths in Thailand and Vietnam but, like sheep Orf on a handlers hand, it failed to adapt within the human to cause onward human to human transmission.
The Sars epidemic of 2003 was frightening as that virus did make it successfully from animal to human and then between humans. In retrospect we were fortunate that the infection was relatively weak and that relatively few of those infected died. Had it been as infectious as influenza the death toll would have been much higher. We have a lot to thank adaptation of virus and host for. Were it not the norm then an epidemic in any one species could signal subsequent epidemics elsewhere. Events such as the Sars outbreak would not be the rare events they are, and life would be both precarious and short.
The history of viruses coupled with their opportunist nature means we will never be rid of transient and unpredicted epidemics. As a virus cools in its virulence and a host eases in its immune response, a variant able to make more progress for a while will periodically displace it. Equally, it has been suggested that pushing a virus wholly out of a population, as occurs following deliberate and widespread vaccination, could leave open an environmental niche to be re-occupied by a new more deadly virus. To date, this last concern has not been borne out in practice. There has not been a 'new' smallpox since its eradication in 1977 and a world almost free of polio has not seen any other virus take its place. Based on those models vaccination to provide a barrier that prevents the initial infection continues to be the first choice for the control of infections that are endemic. But vaccination is not a complete solution. Thirty years after the isolation of HIV the disease looks unvaccinatable, at least in the form we currently think of vaccines. And the problem of unexpected epidemics remains. A vaccine against Sars is now a possibility but before the outbreak the need was not apparent. In these cases a mix of constant vigilance and rapid action to minimise spread, as occurred in Sars, is the way in which the peaks of virus activity can be dampened and the effects of epidemics kept in check.
Chemistry, through the development of general antiviral agents, holds special promise. Although viruses are diverse they can be grouped based on shared features. The way in which they replicate inside a cell is one of them. Although a virus must use cellular processes, there is usually a level of specificity for their own replication over and above that of the host. The level of distinction is slight and can require atomic detail of the relevant virus and host cell proteins to distinguish it but it does occur. Homing in on such differences can allow the development of antiviral drugs that show remarkable specificity for the infected cell. The current drug therapy for HIV infection was generated in exactly this way. Key proteins involved in virus growth, such as the viral protease, had their structure solved at atomic resolution and inhibitors of action were then modelled from the revealed substrate binding pocket. This kind of strategy has also generated the new class of inhibitors for influenza virus offering the potential to stockpile ahead of a pandemic outbreak. In the main, these drugs are highly virus specific but general antiviral drugs able to suppress a variety of virus infections could be developed based on the shared properties of viruses.
Ribavirin, licensed in 1986, is one such chemical. Its mode of action is unique in that it appears to increase the mutation rate of viruses such that they slip over the threshold of life into oblivion. Too many mutations occur in the drug's presence and the virus cannot maintain enough viable copies to ensure onward replication, so it rapidly becomes extinct. A class of drugs working on common viral traits, like mutability, could offer a general treatment for viruses much like antibiotics offer for bacterial infection. A therapy that slowed virus replication to allow time for the host immune response to kick in and mop up would be a valuable resource at the time of epidemics. Riding the waves of virus outbreaks, learning from every event, coupled with surveillance and the development of general virus suppressive agents offers the best hope of moderating the inevitability of virus epidemics rather than being crushed by them.
Ian Jones is Professor of Virology at the University of Reading
On viruses and their effects:
1. All the virology website
2. Jenner Museum website
University of Reading
Virology information on the Internet
History of smallpox
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