Birdflu Mailing List: Scientists Hope Vigilance Stymies Avian Flu Mutations

[William Weir (weirwilliam]

http://www.nytimes.com/2007/03/27/health/27flu.html?ex=1181188800&en=605fe40673e04a75&ei=5070<http://www.nytimes.com/2007/03/27/health/27fluhtml?ex=1181188800&en=605fe40673e04a75&ei=5070>

Scientists Hope Vigilance Stymies Avian Flu Mutations 

By DONALD G. McNEIL 
Jr.<http://topics.nytimes.com/top/reference/timestopics/people/m/donald_g_jr_mcneil/index.html?inline=nyt-per>

New York Times, March 27, 2007

Just exactly what is the bird 
flu<http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/avianinfluenza/index.html?inline=nyt-classifier>
 virus doing?Skip to next paragraph  The virus, H5N1, which was first isolated 
in humans in 1997, has not started a pandemic in a full decade of trying, so a 
few 
flu<http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/influenza/index.html?inline=nyt-classifier>
 experts think it never will.

But the mainstream view is less optimistic. Viruses mutate constantly, many 
experts point out. And when one has already acquired the ability to jump 
species, occasionally spread from human to human and kill 60 percent of the 
people who catch it, it is far too early to dismiss it. 

So even though the human death toll from H5N1 is still below 200, scientists 
around the world are racing to study the ways in which it might mutate to 
spread easily among humans.  The 1918 Spanish flu, they argue, was not even 
noticed until it had killed thousands. It might have been gathering virulence 
for years, hidden in the background of seasonal flu deaths. 

Today's H5N1 flu is probably changing more slowly, because health officials 
have been vigilant about attacking clusters of cases, which presumably wipes 
out the most dangerous strains. Whenever several human cases appear, even in 
remote villages in Indonesia or Egypt, local officials and World Health 
Organization<http://topics.nytimes.com/top/reference/timestopics/organizations/w/world_health_organization/index.html?inline=nyt-org>
 teams move in to kill all the local poultry and dose all the humans with 
antiviral drugs - the so-called Tamiflu blanket strategy.

Each stifled outbreak robs the virus of the chance to carom wildly through 
dozens of human hosts as it does in a flock of chickens or ducks. That fends 
off what virologists most fear: gene-swapping in people infected with both 
human and avian flu. 

But the Tamiflu blanket may not be able to smother every spark, especially if 
countries cannot get their poultry epidemics under control.

A human-bird hybrid strain has not yet been seen in nature. But if it did 
surface, that "would mean we might have a big problem on our hands," said Dr. 
Nancy Cox, chief of the influenza branch of the Centers for Disease Control and 
Prevention<http://topics.nytimes.com/top/reference/timestopics/organizations/c/centers_for_disease_control_and_prevention/index.html?inline=nyt-org>.

Last year, Dr. Cox and colleagues created a hybrid in their lab between a human 
flu of the H3N2 strain and samples of the H5N1 virus collected from 1997 to 
2004. They infected ferrets with it to see if it would spread to ferrets in the 
same cage or those in nearby cages. The hybrid strain proved less lethal and 
was transmitted only once after long contact.

But nature has a bigger laboratory than the CDC does, and the agency's 
director, Dr. Julie L. Gerberding, says the results do not mean that H5N1 
cannot become more infectious. "They mean it's probably not a simple process," 
she said.

Dr. Anne Moscona, a flu expert at Weill Cornell Medical 
Center<http://topics.nytimes.com/top/reference/timestopics/organizations/n/new_york-presbyterian_hospital/index.html?inline=nyt-org>,
 was more emphatic in arguing that there is still reason to worry. "It would 
have been truly ominous if a monster virus had been created by these 
supersimple swaps," she said. "But of three ferrets, one got the virus. Is 33 
percent nothing?"

Geneticists at the University of 
California<http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_california/index.html?inline=nyt-org>,
 Irvine, concluded that the H5N1 flu originated in Guangdong Province in 
Southern China, where millions of people and chickens live in close proximity. 
Guangdong is also believed to be the likely birthplace of previous flu strains 
- even if they later picked up names like "Hong Kong flu" - and to be where the 
SARS<http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/sarssevereacuterespiratorysyndrome/index.html?inline=nyt-classifier>
 virus jumped from horseshoe bats to masked palm civets to humans.

But flus mutate incessantly wherever they move, and in viral samples from Asia, 
the Middle East and Africa, many individual changes that look potentially 
dangerous have been spotted.

In May 2005, for example, the virus in China escaped in migratory birds going 
north and traveled across Russia, Europe and Africa. It became known as the 
Qinghai strain after the lake in Northern China where thousands of ducks and 
geese were found dead. (The older strain in Southern China and Southeast Asia 
is sometimes called the Fujian strain.)

The Qinghai strain has a mutation known as PB2 E627K. (The abbreviation can be 
read this way: at position No. 627 on polymerase basic protein 2, the amino 
acid called glutamic acid, abbreviated by scientists as E, has been replaced by 
lysine, known as K.)  The change helps the virus grow at the temperatures found 
in human noses, which are cooler than the insides of birds' intestines.

It is "characteristic of a gene that's been in mammals," said Dr. Robert G. 
Webster, a virologist at St. Jude Children's Research Hospital in Memphis. "It 
says to me that it was in a mammalian species in China, and got back into 
ducks. But what species? We don't know."  The Qinghai strain has now reached 
about 50 countries.

To give a sense of how important such a tiny change can be: switching just one 
of the 1,255 amino acids in the SARS virus protein that attached to cells in 
the masked palm civet, a relative of the mongoose that is sold in wild-meat 
markets in Asia, allowed it to attach to human cells.

After that discovery, the Chinese government ordered that all the 10,000 civets 
in captivity in Guangdong be killed, thus probably wiping out the disease 
everywhere except in bats.

In avian flu, two mutations known to help viruses spread more easily - because 
they attach to the receptors in human noses and throats instead of those deep 
in the lungs - were found in outbreaks in Azerbaijan and Iraq in 2006. But 
those outbreaks were snuffed out. 

Another mutation, increasingly common in Egypt, where the disease is still 
raging through poultry and occasionally infecting humans, is called M230I. 
Scientists do not know what it does, but its persistence is worrisome, says 
Henry L. Niman, a Pittsburgh biochemist who runs a Web site tracking the 
genetics<http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/geneticsandheredity/index.html?inline=nyt-classifier>
 of flu cases.  M230I is also found in typical annual flu strains like H1N1, 
H3N2 and influenza B; in H7 flus, which pass easily from birds to humans but 
usually cause nothing more serious than pinkeye; and in H3N8, the flu that has 
spread from dog to dog in many American kennels, often fatally.

All the human cases in Egypt with M230I have been fatal, Dr. Niman said, and 
those without it have not been, although that may be coincidence.  Mutations 
that confer resistance to Tamiflu have also been found in Egypt. 

Any antiviral resistance is worrisome because the world still has very few 
weapons against the flu. H5N1 long ago became resistant to older "M2 
inhibitors" like amantadine, possibly because farmers in China are suspected of 
feeding those drugs to their chickens in the late 1990s.

Tamiflu is in another class, known as neuraminidase inhibitors, including 
Relenza and peramivir.  After Tamiflu resistance was found in Egypt, the World 
Health Organization, moving to stave off panic, said the same change was seen 
in Vietnam years before. Still, the Vietnam cases led doctors to start doubling 
the typical Tamiflu dose, effectively halving the world's stockpiles of it.

An American Navy research lab in Cairo found that two Egyptian cases had a 
dangerous mutation known as N294S even before they got Tamiflu. That implies 
that it exists in Egyptian poultry, though it has not been found yet.

Every flu virus is different, and it is impossible to predict exactly what 
constellation of changes will turn one into a pandemic strain.

Dr. Cox and Dr. Ruben Donis, the influenza branch's chief virologist, said they 
would be most worried if they saw spontaneous human-avian crossovers like those 
they created, or if they saw multiple changes in the virus's hemagglutinin 
gene, the attachment "spike" on the virus's shell.   "We're looking very, very 
carefully at the viruses that exhibit changes at the receptor binding pocket," 
Dr. Cox said. "But it's clear that these single changes don't allow the virus 
to move from person to person efficiently." 

And even if H5N1 fails to become a pandemic, Dr. Webster of St. Jude in Memphis 
has what he styles his "hit list" of others waiting their turn.  They include 
H7N7, which infected 89 chicken industry workers in the Netherlands in 2003 but 
killed only one veterinarian; H9N2, which he says is in "every poultry house in 
Eurasia" and causes no symptoms but every once in a while jumps into 
immuno-suppressed people; and H2N2, which is in the wild bird population in the 
United States.