United Press International - September 26, 2002
Charles Q. Choi, UPI Science News

Not only might this help explain why some people infected with HIV can remain healthy for decades, but synthetic versions of this protein also could lead someday to new AIDS-combating treatments.

"This is something that we're studying not just for therapy, but for preventing the infection in the first place," researcher David Ho, director of the Aaron Diamond AIDS Research Center in New York, told United Press International. "They could help improve vaccines."

Sometimes a person infected with HIV can remain healthy for many years without developing AIDS, Ho explained. This group makes up 1 to 2 percent of the 850,000 to 950,000 HIV-infected people in the United States.

Since 1986, scientists have known certain white blood cells in AIDS-free HIV-infected patients secrete biochemicals that somehow prevent HIV from replicating. Despite extensive research, however, the identity of this substance has proven a mystery. Because it comes from the immune cells known as CD8 "killer" T-cells -- which kill infected tissues in the body -- the enigmatic compound was termed CD8 antiviral factor, or CAF.

Possible candidates for CAF have abounded for years. In 1995, "it seemed the mystery was solved" when scientists found proteins that almost fit the bill known as beta-chemokines, Ho said. Although they suppressed HIV to some degree, investigators quickly found beta-chemokines could not explain much of CAF's protective power because they were ineffective against many strains of the virus.

Now investigators have identified proteins that are active against all strains of HIV. Scientists "are already pursuing new therapeutic approaches based on the data," said researcher David Ho, director of the Aaron Diamond AIDS Research Center.

"This discovery is a major step forward in our understanding of how the body fights HIV," lead researcher Linqi Zhang said in a statement. "By understanding how some people's immune systems are able to control HIV infection, we may be able to develop new treatments that take advantage of this phenomenon."

Using sensitive new protein analyzers, Zhang and Ho's team found all AIDS-free HIV-infected patients studied secreted three chemicals that were absent in people developing AIDS. Biochemical experiments and searches of U.S. and European protein databases revealed these chemicals were antibiotics known as alpha-defensins-1, -2 and -3. These germ-killers also attack herpes and flu viruses.

Purified human versions of alpha-defensins reduced HIV replication by 50 to 60 percent, although Ho said it seems you need a minimum of two alpha-defensin types working together to have anti-HIV activity. Synthetic alpha-defensins also reduced HIV activity although they were 10 to 20 times weaker than the natural versions.

Zhang and his colleagues currently are trying to increase their understanding of the HIV-fighting mechanism by which these proteins work -- they do not seem to attack HIV's surface as they do herpes and flu viruses. Because the alpha-defensins are relatively large molecules, they can be cumbersome to use, Ho said.

"We would like to see if we could make a smaller version that would be more powerful, and practically speaking, that would have a better chance of being a therapeutic," Ho said. "This is not going to be the ultimate solution, but it's another weapon we can use in our arsenal against HIV.

Susan Plaeger, chief of the National Institute of Allergy and Infectious Disease's AIDS research branch, found Zhang and Ho's work "exciting, but I don't think it's the absolute answer." Other biochemical factors may also be at work, she said. "I don't know if these molecules are definitely responsible for the activity of CAF. But this is very good work that needs to be followed up. There could definitely be other factors bound up here."

The findings were published online in the September 26 issue of the journal Science.
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