New target in flu virus may open route to better drugs
Researchers have discovered that the influenza A virus makes a protein called NS1 that undermines the body's natural defenses. They found that it binds to an important cell protein - DDX21 - that would otherwise be able to stop the virus multiplying and spreading.
Robert Krug, a professor in the College of Natural Sciences at the University of Texas at Austin, and colleagues suggest NS1 offers a potentially good target for drugs to fight influenza A.
They report their findings in the journal Cell Host & Microbe.
There are three types of flu virus: influenza A, B and C. Type A is the most frequent cause of the flu outbreaks that infect millions of people and claim up to half a million lives worldwide every year.
When a flu virus enters a human cell, it sets about changing the cell's machinery into a factory to replicate itself.
We need new anti-flu drugs because vaccines are not 100% effective and influenza A viruses are developing resistance to drugs currently in use.
Virus protein NS1 gets around human body's anti-flu attack
With his colleagues, Prof. Krug found that while the human body tries to stop the virus from making copies of itself by launching a protein called DDX21, the virus makes a counter-attack using a protein of its own, NS1, which binds to DDX21 and disables it.
The researchers say blocking a protein produced by the influenza virus could provide a route to new flu drugs.
If you could work out how to stop NS1 from binding to DDX1, "you could stop the virus cold," he says.
However, Prof. Krug and his co-authors also found that the virus protein goes further than just countering the attack posed by DDX21. It also carries out other important roles such as blocking the host cell's ability to make interferon, another important antiviral protein.
"It means that if you could block that NS1 function, you'd be blocking not only its interaction with DDX21 but many other important functions, so it's a great target," he adds.
In their study, they found that NS1 was often bound together with DDX21 in infected human cells, which made them curious as to what role the human cell protein might play in virus replication.
So they started by silencing the gene that codes for DDX21, using a technique called siRNA, to stop human cells being able to make the protein.
They found that in the absence of the host cell protein DDX21, the virus increased its replication rate 30-fold.
It was an exciting moment, says Prof. Krug, adding: "That told us that DDX21 is a host restriction factor, that it inhibits replication. That was the key to understanding what was happening."
NS1 viral protein foils human body's defenses in more than one way
In another part of the study, the team discovered that the human cell protein DDX21 does something else that hinders virus replication - it binds to a viral protein called PB1, which helps the virus makes copies of itself.
But, as the researchers discovered in a final step of the study, by binding to DDX21, the viral protein NS1 frees up PB1 again so it can help the virus replicate.
Bringing all these results together shows just how important a role NS1 plays in helping the virus get around the human cell's natural defenses against infection, says the team.
A grant from the National Institutes of Health helped to fund the study.
News of this study coincides with a new review that throws into question the stockpiling of current anti-flu drugs Tamiflu and Relenza. The Cochrane Review, published in the BMJ, says there is no solid evidence to support claims that the drugs reduce hospital admissions and complications as a result of flu.
Written by Catharine Paddock PhD
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