A Small Genetic Change Makes Flu Virus Deadly

A tiny change in one of the influenza virus's 10 genes is key to making certain strains of the virus especially virulent to humans, scientists report in the Sept. 7 issue of Science. This discovery helps explain why an influenza outbreak four years ago in Hong Kong killed an unusually high proportion of the people it infected �� six out of 18, says lead researcher Yoshihiro Kawaoka, D.V.M., Ph.D., of the University of Wisconsin-Madison.

"We have found that a limited number of very tiny genetic changes in a specific gene, one called PB2, can have a big effect on how potent the influenza virus is," says Dr. Kawaoka, a grantee of the National Institute of Allergy and Infectious Diseases (NIAID). "Because the influenza virus constantly mutates, and because only a few changes can make a non-pathogenic virus highly pathogenic, we should assume that an outbreak of any new strain or subtype is potentially dangerous to humans."

"To prepare for future influenza pandemics, NIAID has supported efforts to understand how new virus strains potentially harmful to humans appear," says Anthony S. Fauci, M.D., NIAID director. "This study is an elegant example of research that provides insight into the emergence of virulent viruses and can help us develop better strategies for detecting future outbreaks."

Wild waterfowl are natural reservoirs for the influenza virus; these birds transmit the virus to pigs or chickens, which then pass it on to people. The deadly outbreak of influenza virus subtype H5N1 in Hong Kong in 1997 was the first documented case of an influenza virus jumping directly from chickens to people. Public health authorities responded by ordering the slaughter of more than 1 million live poultry to prevent further spread of the virus to humans.

Dr. Kawaoka and colleagues obtained samples of the H5N1 viruses that had infected Hong Kong residents during the 1997 outbreak. Testing these viruses in laboratory mice, the researchers found good correlation between how sick certain H5N1 strains made mice and how sick they had made humans. The researchers divided the H5N1 strains into two groups: one that caused systemic lethal infection in the mice and one that was relatively benign. Mice are a good model for studying H5N1, Dr. Kawaoka says, because this virus affects mice and humans similarly.

Next, Dr. Kawaoka used a technology that allows him to genetically engineer "designer" influenza viruses from scratch. By systematically swapping the genes from the harmful and benign viruses, then testing how those engineered viruses affected mice, he discovered that the PB2 gene from the harmful group gives the virus its potency. Then, through testing viruses that contained variations of this PB2 gene, he further identified a tiny change within the gene �� a change of just one unit of RNA �� that appears to be key to the virus's virulence.

The function of the PB2 gene is not completely understood, but scientists believe it codes for an enzyme that helps force the host cell's molecular machinery to make more viruses, Dr. Kawaoka explains. "We don't know if the mutation we studied is involved in that process, but our next step will be to find out," he says.

Just over 10 years ago, researchers developed the ability to genetically engineer influenza viruses, a process known as reverse genetics. In 1999, Dr. Kawaoka, with support from NIAID, streamlined this technology, making it much more efficient. Without the ability to engineer influenza viruses through the reverse genetics system, it would not have been possible to create and study variations of the H5N1 virus, Dr. Kawaoka says. "Just a few years ago, this discovery would not have been possible," says Carole Heilman, Ph.D., director of NIAID's Division of Microbiology and Infectious Diseases. "We believe this is the first of many more important discoveries that will arise from this technology."

For more information on Dr. Kawaoka's work in this field, other NIAID-supported influenza research, and background on the virus itself, visit Focus on the Flu on the NIAID Web site at http://www.niaid.nih.gov/newsroom/focuson/flu00. Focus on the Flu also contains information on NIAID-sponsored efforts to prepare for future influenza pandemics. Such efforts include helping to fund ongoing monitoring of influenza virus strains circulating through live poultry markets in Hong Kong, a project that could nip future outbreaks in the bud. Other NIAID-supported researchers are examining the history of influenza virus evolution for clues about which new strains might emerge next.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov. Reference: Hatta M et al. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293(5536):1840-42 (2001). The National Institute of Allergy and Infectious Diseases is a component of the National Institutes of Health, U.S. Department of Health and Human Services