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January 25, 2001 - VOL. 28, NO. 01

UT Austin scientist seeks new molecular clues to fight flu virus


Caroline Ladhani and Mary Lenz


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When cold and drizzly weather strikes, the flu virus follows, typically afflicting up to 20 percent of the U.S. population. While most sufferers experience fever, nausea and muscle pain, influenza epidemics can be deadly, causing as many as 20,000 to 40,000 U.S. fatalities in a normal year.

To be effective against new strains of influenza, flu vaccines must be made fresh every year, but the process can take months, and the difficulties in that approach can be seen in this year's vaccine shortages. Researchers at UT Austin are seeking better, faster ways to attack the flu virus, referred to as antiviral therapies.

Dr. Robert M. Krug, a professor at the Institute for Cellular and Molecular Biology at The University of Texas at Austin, is seeking new clues to ways the flu virus operates at the genetic and molecular levels to take over functions of its host cell. Krug's work eventually could lead to the discovery of ways to block flu virus from reproducing itself once a cell has become infected.

Krug, who served for nine years as chair of the molecular biology and biochemistry department at Rutgers University, joined UT Austin's College of Natural Sciences as a research scientist this year. He explained that, like other viruses, the influenza virus is a parasite. That means the flu virus can only reproduce and carry on its metabolic processes inside a living cell, its host cell.

To find the best targets for treatment, Krug is studying the molecular mechanisms that enable the flu virus to manipulate the host cell in order to duplicate its own genetic information.

Krug's lab has shown that influenza virus is unique among animal viruses because it cannibalizes normal RNA in the nucleus of an infected cell. (RNA, or ribonucleic acid, acts as a messenger translating the instructions from DNA into protein.) By hijacking part of the cellular messenger, influenza virus can synthesize the viral RNAs that direct the synthesis of viral proteins.

This hijacking is carried out by a viral enzyme called RNA polymerase, which synthesizes viral messenger RNAs. Krug has begun a new approach to develop antiviral agents that are directed against this crucial enzyme.

Another major focus of Krug's research is a particular virus-encoded protein known as NS1, which he believes may be a key to stopping cells from fighting off the virus once they are infected. The NS1 protein is not part of the virus but is synthesized in infected cells once the virus starts acting.

In cells infected with flu, the newly synthesized NS1 protein soon takes control of several normal cellular functions. For example, NS1 binds to and inhibits the activity of two proteins located in the host cell's nucleus. This, in turn, inhibits the export of cellular RNA messengers to the cell's cytoplasm, where these messenger RNAs normally would direct the synthesis of cellular proteins. Instead, these cellular messenger RNAs are degraded in the nucleus.

This is the mechanism the virus uses to stop the cell from making proteins that ordinarily would protect the cell.

Krug is determining whether specific antiviral agents can be developed to block this function of the flu NS1 protein -- thereby allowing the cell to manufacture virus-fighting proteins.

The difference between anti-viral agents and flu vaccines is that anti-virals act on the virus just before or after it attacks the cell, while flu vaccines are taken weeks ahead of exposure, causing the production of antibodies that stop the virus from ever getting into the cell.

That means as soon as an epidemic starts, antiviral agents can be used by high-risk or crowded populations, including the elderly, health care workers, the military and college students.

Unfortunately, flu vaccines must be reformulated each year from dead flu virus because viral proteins usually change, Krug said, "rendering the previous year's vaccine ineffective against the new strain." Producing new vaccine can take as long as six months, which, Krug said "can be too long to control a fast-moving epidemic."

When a super-epidemic (called a pandemic) occurs, or when an especially dangerous strain appears delay can be deadly.

"Antivirals can be rapidly employed to combat an epidemic," Krug said. "The efficacy of antiviral therapy against influenza virus has been greatly enhanced because the virus can be detected at an early time of infection, using rapid diagnostic tests." Krug said with vaccines, "you have a problem because you have to make a new one every year and when there's a pandemic, you have to make a large amount."


January 25, 2001
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