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http://www.nytimes.com/2009/06/09/health/09flu.html?bl&ex=1244779200&en=7d3c3a6c549a733a&ei=5087
How a Mild Virus Might Turn Vicious
By DONALD G. McNEIL Jr.
Published: June 8, 2009
The swine flu virus is rapidly making its way around the world, but it has been relatively mild so far, causing only 139 confirmed deaths. Could it mutate into something more lethal?
Scientists looking at its genetic structure say there is no obvious pressure for it to do so ? no reason for this virus to ?want,? in the Darwinian sense, to kill more of its hosts.
It is already doing a near-perfect job of keeping itself alive by invading human noses and inducing humans to cough it from one to another, said Dr. W. Ian Lipkin, director of the Center for Infection and Immunity at Columbia University?s Mailman School of Public Health.
?A really aggressive flu that quickly kills its host? ? like SARS and H5N1 avian flu ? ?gives itself a problem,? Dr. Lipkin said.
But flu viruses are highly mutable, and anything could happen in the next two years, the time a new strain normally takes to circle the globe. After all, Spanish influenza began as a mild strain, then turned horrifically virulent, killing 20 million to 100 million people in 1918-19.
But Dr. Peter Palese, head of microbiology at Mount Sinai Medical School and part of the team that rebuilt that virus in 2005 from fragments found in old lung tissue, said that strain was a ?once-a-millennium or once-every-10-millennia event ? things like it don?t happen very often.?
Nor is it clear, he added, that viruses really ?want? a particular outcome.
?For me, that?s too much anthropomorphic thinking,? Dr. Palese said. ?Look, I believe in Darwin. Yes, the fittest virus survives. But it?s not clear what the ultimate selection parameter is.?
A mutation that confers lethality, he explained, may confer another advantage scientists have not pinned down.
The new virus has been described as ?a real mutt? by Walter R. Dowdle, the former chief of virology for the Centers for Disease Control and Prevention, because of its unique mix of Eurasian and American swine, human and bird genes.
Flu chromosomes are quite simple ? eight short strands of RNA that issue the genetic code for a grand total of 11 proteins. They break apart in a jumble inside cells they infect, and then they reassemble, picking up random bits of other flus, which makes the results unpredictable.
The current swine flu strain lacks several genes believed to increase lethality, including those that code for two proteins known as PB1-F2 and NS-1, and one that codes for a tongue-twister called the polybasic hemagglutinin cleavage site.
PB1-F2 appears to weaken the protective membrane of the energy-producing mitochondria in an infected cell, ultimately killing the cell. Specifically, it attacks dendritic cells, the sentinels of the immune system. Its lethality could be accidental ? a protein good at killing sentries might just go on killing other cells once inside the fort.
All pandemic flus, including those of the Spanish, Hong Kong and Asian flus, make PB1-F2. So does the H5N1 bird flu. The current swine strain does not.
The NS-1 protein also maims the immune response by blocking interferon, an antiviral protein made by cells.
Very lethal bird flus also have the unusual cleavage site, which allows the hemagglutinin spike on the virus?s shell to split and inject its genetic instructions into different kinds of cells, like those in the lungs and the gut.
Such an addition to the novel H1N1 would be very dangerous. But because it has been found only in avian flus, it is unlikely to become a component of a human flu, Dr. Palese said. Even the 1918 virus, which was avian in origin, lacked it.
A much more likely change, scientists have said, is that the H1N1 swine flu will become resistant to the antiviral drug Tamiflu. A gene for Tamiflu resistance is now almost universal in seasonal H1N1 flus.
If that happens, the world?s Tamiflu stockpiles will be all but worthless, and doctors may have to switch to Relenza, which is a powder used with an inhaler, which makes it more expensive and harder to take.
Depending on the mutation, older antiviral drugs like rimantidine may be useful, but so much resistance to them developed in seasonal flu that they were largely abandoned a few years ago.
Dr. Palese was asked about another notion concerning likely mutations. There has been outrage at Egypt?s decision to kill all the pigs belonging to its Coptic Christian minority. It has been depicted as misguided and motivated by religious bigotry, because the ?swine flu? is really now a human flu.
But Egypt is also in an especially dangerous situation. The new swine flu reached it just last week. The H5N1 avian flu has circulated in its backyard chickens since 2006, defying all eradication efforts. In the last year, dozens of H5N1 cases have been confirmed in toddlers, almost all of whom have survived ? which led some experts to speculate that those are cases of a less lethal version of H5N1 that is better adapted to humans.
In that case, might it be wise to get rid of the country?s relatively small pig population, since pigs are ?mixing vessels? that can catch both human and bird flus?
?I agree with the premise, if you really could eliminate an animal reservoir,? Dr. Palese said. ?But the virus is out of pigs now ? and it?s more important that those poor people have something to eat.?
How a Mild Virus Might Turn Vicious
By DONALD G. McNEIL Jr.
Published: June 8, 2009
The swine flu virus is rapidly making its way around the world, but it has been relatively mild so far, causing only 139 confirmed deaths. Could it mutate into something more lethal?
Scientists looking at its genetic structure say there is no obvious pressure for it to do so ? no reason for this virus to ?want,? in the Darwinian sense, to kill more of its hosts.
It is already doing a near-perfect job of keeping itself alive by invading human noses and inducing humans to cough it from one to another, said Dr. W. Ian Lipkin, director of the Center for Infection and Immunity at Columbia University?s Mailman School of Public Health.
?A really aggressive flu that quickly kills its host? ? like SARS and H5N1 avian flu ? ?gives itself a problem,? Dr. Lipkin said.
But flu viruses are highly mutable, and anything could happen in the next two years, the time a new strain normally takes to circle the globe. After all, Spanish influenza began as a mild strain, then turned horrifically virulent, killing 20 million to 100 million people in 1918-19.
But Dr. Peter Palese, head of microbiology at Mount Sinai Medical School and part of the team that rebuilt that virus in 2005 from fragments found in old lung tissue, said that strain was a ?once-a-millennium or once-every-10-millennia event ? things like it don?t happen very often.?
Nor is it clear, he added, that viruses really ?want? a particular outcome.
?For me, that?s too much anthropomorphic thinking,? Dr. Palese said. ?Look, I believe in Darwin. Yes, the fittest virus survives. But it?s not clear what the ultimate selection parameter is.?
A mutation that confers lethality, he explained, may confer another advantage scientists have not pinned down.
The new virus has been described as ?a real mutt? by Walter R. Dowdle, the former chief of virology for the Centers for Disease Control and Prevention, because of its unique mix of Eurasian and American swine, human and bird genes.
Flu chromosomes are quite simple ? eight short strands of RNA that issue the genetic code for a grand total of 11 proteins. They break apart in a jumble inside cells they infect, and then they reassemble, picking up random bits of other flus, which makes the results unpredictable.
The current swine flu strain lacks several genes believed to increase lethality, including those that code for two proteins known as PB1-F2 and NS-1, and one that codes for a tongue-twister called the polybasic hemagglutinin cleavage site.
PB1-F2 appears to weaken the protective membrane of the energy-producing mitochondria in an infected cell, ultimately killing the cell. Specifically, it attacks dendritic cells, the sentinels of the immune system. Its lethality could be accidental ? a protein good at killing sentries might just go on killing other cells once inside the fort.
All pandemic flus, including those of the Spanish, Hong Kong and Asian flus, make PB1-F2. So does the H5N1 bird flu. The current swine strain does not.
The NS-1 protein also maims the immune response by blocking interferon, an antiviral protein made by cells.
Very lethal bird flus also have the unusual cleavage site, which allows the hemagglutinin spike on the virus?s shell to split and inject its genetic instructions into different kinds of cells, like those in the lungs and the gut.
Such an addition to the novel H1N1 would be very dangerous. But because it has been found only in avian flus, it is unlikely to become a component of a human flu, Dr. Palese said. Even the 1918 virus, which was avian in origin, lacked it.
A much more likely change, scientists have said, is that the H1N1 swine flu will become resistant to the antiviral drug Tamiflu. A gene for Tamiflu resistance is now almost universal in seasonal H1N1 flus.
If that happens, the world?s Tamiflu stockpiles will be all but worthless, and doctors may have to switch to Relenza, which is a powder used with an inhaler, which makes it more expensive and harder to take.
Depending on the mutation, older antiviral drugs like rimantidine may be useful, but so much resistance to them developed in seasonal flu that they were largely abandoned a few years ago.
Dr. Palese was asked about another notion concerning likely mutations. There has been outrage at Egypt?s decision to kill all the pigs belonging to its Coptic Christian minority. It has been depicted as misguided and motivated by religious bigotry, because the ?swine flu? is really now a human flu.
But Egypt is also in an especially dangerous situation. The new swine flu reached it just last week. The H5N1 avian flu has circulated in its backyard chickens since 2006, defying all eradication efforts. In the last year, dozens of H5N1 cases have been confirmed in toddlers, almost all of whom have survived ? which led some experts to speculate that those are cases of a less lethal version of H5N1 that is better adapted to humans.
In that case, might it be wise to get rid of the country?s relatively small pig population, since pigs are ?mixing vessels? that can catch both human and bird flus?
?I agree with the premise, if you really could eliminate an animal reservoir,? Dr. Palese said. ?But the virus is out of pigs now ? and it?s more important that those poor people have something to eat.?
