Anti-HIV Find Is Revealed--and Quickly Disputed
New York researchers report today that they have identified a mysterious and long-sought family of proteins that protect some people infected with HIV from progressing to AIDS, but their report has drawn quick criticism from others involved in the search.
Dr. David Ho and his colleagues at the Aaron Diamond AIDS Research Center say that a group of three proteins called alpha-defensins are produced in the white blood cells of so-called long-term non-progressors and that these proteins block the replication of HIV in the test tube.
If their findings are correct, it would open the door to a new approach to therapy that would not involve the use of powerful yet toxic drugs.
But other researchers say Ho is wrong.
“We have looked at defensins in the past,” said Dr. Jay Levy of UC San Francisco, who was the first to recognize the presence of a protein that blocks HIV replication in non-progressors and who has spent the last 16 years searching for it. “It is not defensins.”
“I guarantee you that their interpretation of their data is wrong,” added Dr. Robert Gallo, head of the Institute of Human Virology in Baltimore, who was a co-discoverer of the AIDS virus. In fact, Gallo says, he has identified the protein sought by Levy and others in his own lab but has delayed publication until his team can document its properties more thoroughly.
Levy said his team also is “very close” to identifying the elusive factor, which he calls CD8 antiviral factor, or CAF. Defensins, he said, may have a small anti-HIV effect, but they do not have the properties that would be expected for CAF.
The entire argument over whether defensins are CAF may, in fact, be irrelevant, added Dr. Robert Lehrer of UCLA, whose team discovered defensins in 1985. “Does it matter what you call it, or does it matter what it is and what it does?” he said. “Is this a possible explanation for why some people are better defended against HIV than others? Probably.”
An estimated 5% to 10% of people who are infected by HIV are able to naturally suppress viral replication and never develop AIDS symptoms. Researchers know how they do it in many cases. Some people lack a receptor on immune cells called CCR-5, which allows HIV to bind to and infect the cells. Others have certain combinations of so-called histocompatibility, or HLA, antigens that seem to preclude progression. Some have white blood cells that produce a combination of chemicals called beta-chemokines, identified by Gallo in 1995, that inhibit viral replication.
“What’s most important is that these factors vary enormously ... from one long-term non-progressor to another,” Gallo said. “There is no single answer.”
Most of those factors do not offer new opportunities for therapy, but CAF would seem to do so if it could be identified. Levy first postulated its existence more than 15 years ago, demonstrating that white blood cells called CD8 cells taken from non-progressors secrete a protein that blocks HIV replication.
But “it is very difficult to find a small amount of a protein that is mixed in with thousands of others,” he said.
Ho, Linqi Zhang and their colleagues used a protein analysis system created by Ciphergen Biosystems of Fremont, Calif., to fish out three proteins produced by CD8 cells grown in culture. Together, the three proteins sharply inhibited replication of HIV in the test tube, they are expected to report today in the online version of Science at www.scienceexpress.org.
After isolating and characterizing the proteins, they concluded that they were identical to three previously known proteins called alpha-defensin-1, -2 and -3. These proteins, found in primates, help protect against many types of viral and bacterial infections. Anecdotal reports suggest that some researchers have tried to use defensins against HIV infections, but very little has been published--often a sign that they did not see any startling activity.
Dr. Michael Selsted of UC Irvine, one of the co-discoverers of defensins, questioned the results because the proteins have been shown to be produced by many types of immune cells, but never by CD8 cells. Selsted, Gallo and others argue that the defensins isolated by Ho and Zhang may actually have been produced by other cells that the researchers added to the CD8 cells to help them grow.
“They should have demonstrated that CD8 cells synthesize defensins,” he said. “It was not done. I am amazed that [the paper’s] reviewers did not demand that experiment.”
Levy and others also noted that the antiviral activity reported for the defensins is much smaller than that previously associated with CAF. “It’s not a robust antiviral effect,” he argued.
For the time being, then, it remains unclear whether Ho has found the ultimate protective agent in non-progressors or just one of many.
As he said at a news conference Thursday: “This is not going to be the ultimate solution, but simply another weapon we could use in our arsenal against HIV.”
