-Caveat Lector-

Source: NIH/National Institute Of Allergy And Infectious Diseases
(http://www.niaid.nih.gov)

Date: Posted 9/7/2001

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.

Editor's Note: The original news release can be found at
http://www.niaid.nih.gov/newsroom/releases/genchange.htm

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