Scientists Race to Find
Elusive AIDS Inhibitor
By DAVID HAMILTON
Staff Reporter of THE WALL STREET JOURNAL
Back in 1986, San Francisco AIDS researcher Jay Levy found that the immune system in a few rare individuals produces a mysterious substance that prevents HIV, the deadly AIDS virus, from replicating. For more than 15 years, he and others have struggled to identify it.
Now, the race is heating up. Thanks to new technology for analyzing blood and cell samples, two prominent AIDS laboratories -- at the Aaron Diamond AIDS Research Center in New York and the National Institutes of Health -- believe they may be closer to identifying that substance, and thus explaining why some people can carry the virus in their bodies yet not develop AIDS.
Identifying the substance would yield rich scientific rewards and possibly open up new lines of attack against HIV. Dr. Levy thinks there is a single substance at work, though other researchers believe there may be a number of resistance factors involved.
Success could also prove lucrative for Ciphergen Biosystems Inc., a biological-equipment manufacturer that has taken an unusually direct role in the work. The company specializes in systems that identify proteins, the molecular workhorses of the body, which almost certainly form the basis of any HIV inhibitors. Ciphergen will analyze patient samples for both labs. In exchange, the company gets exclusive commercial rights to any drug or diagnostic treatment that emerges.
There's no way to know what such rights might be worth, but such deals are increasingly common in medical research and may become more so as private companies take the lead in applying automation and computer technology to lab tasks that once required a doctorate in biology.
Ciphergen's protein-detection system can scan through hundreds of unknown proteins, even those present only in tiny quantities, in about an hour. Conventional laboratory techniques can take days or weeks and generally require much larger samples.
"We've never had this level of sophistication" in protein analysis, says Anthony Fauci, director of NIH's National Institute of Allergies and Infectious Diseases.
Of course, there is no guarantee that even faster and more efficient protein scanning will yield the prize. The inhibitory factor or factors appear to be surprisingly fragile in a lab and lose their effectiveness after a few days, making them difficult targets even for Ciphergen's equipment.
There is plenty of scientific competition as well. Dr. Levy's team at the University of California at San Francisco continues to pursue the hunt through more traditional methods. His lab is also scanning for differences in gene activity in the T cells of AIDS patients and others who appear resistant to HIV, hoping to find genes responsible for inhibitory proteins.
Meanwhile, HlV co-discoverer Robert Gallo, whose laboratory six years ago isolated a weaker set of HIV-inhibiting proteins known as beta-chemokines, says he has already identified three more inhibitors, at least one of which appears to fit Dr. Levy's description. Dr. Gallo hasn't yet published those findings and declines to describe the work in detail, saying his team is working to characterize the proteins. But, he adds, "We're damn near having the whole thing [HIV resistance] explained, in my view."
Such claims of success by Dr. Gallo haven't dissuaded competing molecular biologists from pursuing similar research, including Tae-Wook Chun, who runs the search in Dr. Fauci's lab, and Linqi Zhang, who does the same at the Aaron Diamond center. "It's a high-risk project," says Dr. Chun. "If we find it, it will be great for research and for infected patients. If we don't find it, that's it."
The inhibitors in question appear to be produced by a particular kind of immune cell known as a CD8+ T cell. To analyze the proteins, researchers make cultures of CD8+ cells taken from "long-term nonprogressors" -- people who don't develop AIDS despite being infected with HIV. By comparing fluids from those samples with others from typical AIDS patients, the scientists hope to pinpoint the proteins that hold the virus at bay.
Such an analysis isn't much more complicated than placing a few drops of that fluid onto one of Ciphergen's protein chips -- long, narrow slides dotted with circular wells. Each well is treated so that it attracts proteins with particular characteristics; those with positive charges, for instance. Only a fraction of all proteins in the sample stick to any one spot, making identification much easier.
At the Aaron Diamond center, Dr. Zhang stands by as a technician pops one of those chips into a slot in the Ciphergen protein analyzer, a largely featureless box somewhat larger than a steamer trunk. Inside a laser zaps a small area of each well, vaporizing the proteins stuck there and sending them flying down a vacuum tube toward a detector. Measuring that time of flight yields the mass of each protein, which in turn can be used to infer the amino acids that make up its structure.
A nearby computer screen shows data from several protein chip readings, a set of straight lines interrupted by seismic jags corresponding to a protein. "That's a non-progressor," says Dr. Zhang, pointing to a series of peaks, each corresponding to a particular protein. Below it, the readout from a more typical AIDS patient is flat in the same locations, marking the proteins in question as targets for investigation. Most times, though, both teams ship their samples to Ciphergen for analysis, which the Fremont, Calif., company does in separate locations to prevent one lab from learning of the results of the other.
Both labs have identified a subset of likely HIV inhibitors from their work. To conclusively identify the inhibitors, both groups must isolate each protein to determine its amino-acid sequence, which in turn will let them identify the gene that produces it.
The scientists would then need to prove that the protein inhibits HIV, which they can test either by adding the protein to cell cultures or by splicing its gene into those cells and observing the effect on HIV.
Newly discovered HIV inhibitors could serve as antiviral drugs if they can be easily manufactured and don't produce toxic side effects. The proteins would also likely shed new light on how HIV infects cells and reproduces, which could lead to new drug targets.
On the other hand, any new inhibitors could be a bust. Bruce Walker, an AIDS specialist at Harvard University who is also hunting for inhibitors, worries that new inhibitors may turn out to be too weak to be of much use in AIDS treatment.
Write to David Hamilton at david.hamilton@wsj.com
Updated April 18, 2002 |
