Scientists Get A Peek Into Flu Virus Defenses

Scientists have mapped out the bit of molecular plumbing that allows the influenza virus to outwit front-line flu drugs, but disagree on exactly how it works

Scientists have mapped out the bit of molecular plumbing that allows the influenza virus to outwit front-line flu drugs, but disagree on exactly how it works, according to a pair of studies released Wednesday.

A detailed understanding of the tunnel-and-gate mechanism, called an ion-channel protein, could lead to new drugs that could block the reproduction of flu viruses inside host cells, the researchers said.

Some 500,000 people around the world die every year from seasonal Influenza A virus, which mutates slightly from one year to the next.

A virus is a sub-microscopic pathogen that can only reproduce inside a host cell. It is composed of discrete viral particles, each with its own RNA, called virions. Like DNA, RNA contains genetic code transferred during reproduction.

When a virion enters the lungs of a bird, a horse or a human, its membrane fuses with material inside a host cell.

Triggered by the acidic low pH of the cell's interior, the virion's RNA enters its host and begins to multiple, wreaking havoc in the process, and provoking the symptoms associated with influenza.

But this mechanism only works if the acidic milieu outside the virus membrance first "leaks" into the virion through the ion-channel, also known simply as M2.

Two anti-flu drugs -- amantadine, sold as Symmetrel, and rimantadine, sold under the brand Flumadine -- were designed to block this process, but over the last 10 years the Influenza A virus has developed a 90 percent resistance to both medications, the studies say.

Using a nuclear magnetic resonance spectroscopy, Jason Schnell and James Chou at the Harvard Medical School show for the first time the detailed structure of the M2 protein.

A team of researchers led by Amanda Stouffer at the University of Pennsylvania, working independently, used another technique called X-ray crystallography to examine that part of the M2 protein through which the transfers from virus to cell take place.

Both studies, published in the British scientific journal Nature, agree on the basic architecture of M2. Where they disagree, notes Christopher Miller of the Howard Hughes Medical Institute in New York, is exactly how the transfer takes place.

"The controversy stems not so much from incongruities in the structural detail," but from very different theories on how M2's channel-and-gate prevents the flu-drugs from working properly, he said in a commentary, also published in Nature.

Schnell and Chou argue that the drug molecules get bound up at the channel's outer surface, while Stouffer's team speculates that the drug is blocked inside the open pore.

The difference is critical, because any new drugs would need to be designed to counteract one or the other mechanism.

Miller also noted inconsistencies and ambiguities in both studies, suggesting more research is needed before the mechanism is fully understood.

Pandemics occur with the emergence of a strain so different genetically that immune systems and vaccines are not be primed to recognise it. The "Spanish flu" of 1918 virus killed as many as 50 million people.

Source-AFP
ANN/K