A Way To Lock Out Aids?

Labs are working on treatments to foil HIV's use of cellular receptors

For Matthew Sharp, the news last year of breakthroughs in AIDS drugs was bittersweet. With great fanfare, researchers had announced in late 1996 and early 1997 that new protease inhibitors, combined with older drugs, reduced the blood levels of the deadly virus to below the limits of detection. Some scientists even dared hope that the drugs, which target one particular viral enzyme, would offer a cure. But Sharp's own experience told him that the new drugs wouldn't work for everyone. The first one he tried failed. Another knocked his virus level down but after a year, "it started coming back," Sharp recalls. Now, a third protease inhibitor appears to be holding the virus in check--but it's still detectable in his blood. The 41-year-old outreach coordinator for San Francisco General Hospital's AIDS program and ACT UP activist lives in constant fear that HIV will flare up again. "We need new targets and new drugs," he says.

Sharp isn't unique. The new drugs aren't holding the virus in check in more than half of AIDS patients treated at some hospitals. And a spate of new studies show that even when the drugs do work, the virus still lurks within many cells, ready to burst into action at any moment. "For a large segment of the population, protease inhibitors are not going to be the solution," warns Steven G. Deeks, a professor at the AIDS program at San Francisco General.

That's why scientists and companies are searching for new therapies. And hopes are high that the next breakthrough will come from rapidly moving research into so-called chemokine receptors, cellular "doorknobs" used by HIV to help gain entry into the T-cells of the immune system. "It's the most exciting new area of anti-HIV research to come along in years," says biotech analyst Michael G. King of Vector Securities International. Robert C. Gallo, director of the Institute of Human Virology at the University of Maryland at Baltimore and co-discoverer of the virus, is even more enthusiastic: "My hope is that this will be the final blow to HIV."

Dozens of academic labs and companies, from small biotech firms such as Progenics Pharmaceuticals in Tarrytown, N.Y., and LeukoSite in Cambridge, Mass., to giants such as Merck and Glaxo Wellcome, are racing to turn the new science into potential treatments (see diagrams). They are searching for drugs capable of covering up and blocking the receptor from the matching HIV protein. Researchers are also concocting ways to stop production of the receptors themselves. And they are engineering friendly viruses to attach to the receptors and kill already infected cells. "The pace of research is tremendous," says Richard Horuk, senior scientist at Berlex Biosciences in Richmond, Calif. "Things are happening so fast that we have to keep checking the Internet to see if anyone has scooped us."

"ZIP CODES." The AIDS discoveries have energized what was a few years ago "a quiet, if promising, area of research," says Patrick Gray, scientific director of ICOS Corp. in Bothell, Wash., who has been working on chemokines since the early 1990s. Scientists knew that chemokines are small proteins that helped control the enormously complex immune system. The flowing traffic of cells is directed by the dozens of different chemokines according to the patterns of the chemokine receptors on the cell surfaces. The receptors "serve like Zip codes for where the cells are designed to go," explains Dan Littman of the New York University Medical Center.

Because these proteins and their receptors play key roles in the immune system, "it's becoming clear that they are terrific targets for a lot of pharmaceutical interventions," says Littman. Already, companies such as Berlex and LeukoSite are developing chemokine receptor-binding drugs to treat multiple sclerosis, arthritis, and asthma.

But the field exploded in 1995 when Gallo, then at the National Cancer Institute, made a landmark discovery. AIDS researchers had known that immune system cells make a mysterious substance capable of inhibiting the virus. Gallo found that the substance was actually a "cocktail" of three chemokines. This year, he found afourth inhibitory chemokine.

Theoriginal breakthrough prompted dozens of AIDS labs to plunge into chemokine research. Within months, scientists at the National Institutes of Health and the Aaron Diamond AIDS Research Center in New York City and at companies such as Progenics and LeukoSite identified which key chemokine receptors were involved. And they put together a detailed picture of how HIV uses them to infect cells. A virus first grabs onto the T-cell by attaching its gp120 protein to a receptor on the cell named CD4 (illustration). But it can't get in without metaphorically grabbing and twisting the chemokine receptor doorknob. That "opens" the door and lets in the deadly virus.

The intriguing implication is that HIV might be stymied by preventing it from grabbing the doorknob. In fact, nature has already shown that the strategy works. Some 1% of Caucasians harbor a mutation in one of their chemokine receptor genes that completely protects them from the most common AIDS virus type. The defect prevents cells from putting one chemokine receptor, called CCR5, on their surfaces, so there is nothing for the virus to grasp. The virus can attach to the CD4 handle, but without the chemokine receptor, it eventually drops off and falls apart--a harmless monster that can rattle the door but not get in.

Medicine's task is to duplicate this natural protection. The main approach is to develop molecules that attach to the chemokine receptors, preventing the virus from grabbing hold. Scientists learned that just adding extra chemokines did the trick in the test tube. When researchers at Progenics first did the test, "it was the kind of incredible experiment you dream about," recalls Dr. Paul J. Maddon, CEO of Pro-genics. "The virus is blocked 100%." But most scientists believe that adding extra chemokines won't work in people because the substances could cause many other effects, including harmful inflammation.

So the search is on for substances that deny HIV access but don't have chemokines' effects. In the past few months, a number of research teams have reported success using modified chemokines, small peptides, and engineered antibodies. And companies are closing in on the ideal treatment: drugs that could be given in pill form. Expect clinical trials by 1999 or 2000, predicts Progenics' Maddon, who has just entered into an agreement with giant Hoffman-LaRoche Inc. to develop such drugs.

Meanwhile, scientists are busy manipulating the chemokine receptor system in other ways. At Wake Forest University's Bowman Gray School of Medicine, cancer biology professor Si-Yi Chen has been able to genetically engineer T-cells to stop them from putting chemokine receptors on their surfaces. The trick is adding the gene for a substance dubbed an intrakine, which grabs these receptors inside the cell and prevents them from making it onto the surface. The result: The virus has nothing to latch on to.

Protecting T-cells with chemokine receptor drugs or gene therapy could prevent HIV from taking hold. However, it won't get rid of viruses that are already inside cells--the requirement for a cure. So some researchers are devising ambitious schemes to kill infected cells. Their approach: design a friendly virus coated with both CD4 and chemokine receptors. The virus can use the same entry system as HIV to get into the infected cell and then kill it. Researchers such as Michael J. Endres of the University of Pennsylvania have already reported progress in making such a killer virus.

END RUN. Of course, there's no guarantee these strategies will work. With chemokine receptor-blocking drugs, the approach that is the furthest along, "the main concern is that if you block one receptor, you may drive the virus to using another one," warns AIDS researcher John P. Moore at Aaron Diamond. Before treating patients with such a drug, "you have to make damn sure you've got inhibitors for the other receptors," he says. While there's no reason such additional inhibitors can't be made, no one knows the side effects of blocking chemokine receptors, which may be very biologically important.

Still, the chemokine strategy offers a major advantage over drugs such as protease inhibitors that attack the virus directly. "The virus can mutate to step around drugs," explains Robert W. Doms of the University of Pennsylvania. "But when you go after a normal cellular protein that the virus needs, it may not be able to mutate as much." That has scientists hoping that treatments based on chemokines will keep HIV under control for decades. Patients such as Sharp can only pray that they are right.

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