Stop  copying   protein to knock out flu virus The influenza A virus makes a protein that helps it outwit one of the body natural defense mechanisms. That protein could be a good target for antiviral drugs, researchers suggest.

Better antiviral drugs could help the millions of people annually infected by flu, which kills up to 500,000 people each year.

When an influenza virus infects a human cell, it uses some of the host cellular machinery to make copies of itself, or replicate.

A new study, published in the journal Cell Host and Microbe, shows a protein produced by human body cells, DDX21, blocks this replication process. A protein created by the virus, NS1, in turn blocks DDX21 and promotes viral replication.

�If you could figure out how to stop NS1 from binding to DDX21, you could stop the virus cold,� says Robert Krug, professor of molecular biosciences at University of Texas at Austin.

In addition to countering the body defense mechanisms, the viral NS1 protein actually performs other important roles for the virus, such as inhibiting the host synthesis of interferon, a key antiviral protein, Krug says.

�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 a great target.�

FAST-SPREADING EPIDEMICS
The need for new antiviral drugs against the influenza virus is great. Because flu vaccines are not 100 percent effective, antiviral drugs play an important role in fast-spreading epidemics. Yet influenza A viruses are developing resistance to antiviral drugs currently in use.

Krug and his team discovered that the viral NS1 protein is often associated, or bound together, with the host DDX21 protein in infected human body cells. To understand what role DDX21 might play in virus replication, the researchers used a technique called siRNA gene silencing to knock down the production of DDX21 in infected cells. When they did, virus replication increased 30-fold.

�That told us that DDX21 is a host restriction factor, that it inhibits replication,� says Krug. �That was the key to understanding what was happening. It was an exciting moment.�

Next, the researchers discovered that DDX21 blocks replication by binding to a protein that the virus needs to replicate, called PB1. Finally, they discovered that NS1 binds to DDX21 and makes PB1 available again for replication.

This result confirmed that NS1 was indeed the countermeasure used by the virus to get around the body natural defense mechanism.

The National Institutes of Health supported the research.