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NOVEMBER 24, 2003
Barring The Door Against AIDS A new generation of drugs focuses on keeping the virus from entering cells At first glance, the war on AIDS is going well. Potent drugs introduced since 1996 have dropped the number of deaths in the U.S. to less than 20,000 a year, from their 1995 peak of 50,000. But the truth is that the battle between man and microbe still rages. New cases of infection continue in the U.S. at a rate of about 40,000 each year -- and the disease is taking a devastating toll in Africa and elsewhere around the world. In addition, the drugs have major limitations. They're expensive and usually complicated to take. Over years of use, they cause potentially life-threatening side effects. And they're being outwitted by the virus, which is developing mutations that enable it to evade the drugs. Existing treatments "are reaching their limit," says Rob Camp, antiviral project director at the Treatment Action Group. Researchers are now fighting back with a slew of novel weapons. Twenty-three of today's 24 approved AIDS drugs tackle HIV at just two points in its life cycle -- both after the virus has already forced its way into cells and hijacked their machinery to reproduce itself. In contrast, "the next major wave of drugs will be entry inhibitors," predicts Dr. Robert C. Gallo, director of the University of Maryland's Institute of Human Virology, and co-discoverer of HIV. By barring the door to HIV, these new therapies, in effect, will try to turn the virus into a toothless monster that can do little more than angrily rattle the cells' door handles. Indeed, adds William A. Haseltine, chief executive of Human Genome Sciences Inc. (HGSI ), "what everyone is hoping is that with one or more drugs added to the cocktail, we may get lifelong remission." MOLECULAR DANCE The new approaches to fighting HIV are the result of a series of discoveries about the intricate molecular dance that the virus performs to force its way into cells. As the microbe floats through the body in the bloodstream, it searches for so-called CD4 cells. These immune-system cells sport natural docking ports, or receptors -- also called CD4 -- on their outer membranes. The virus first uses a protein on its outer coat, named gp120, to stick to the CD4 receptor. That triggers gp120 to change its shape just enough so that it can also bind to a second receptor on the targeted cell, dubbed CCR5. Then comes the final assault. The virus unleashes a protein named gp41 that uncoils to thrust into the cell's membrane like a harpoon. Its defenses breached, the cell wall opens up to allow the deadly viral genes to enter. MUTATION FEARS Uncovering the details of this molecular siege has enabled researchers to design drugs to block the microbe at each step. Bristol-Myers Squibb Co. (BMY ) and Progenics Pharmaceuticals Inc. (PGNX ), for instance, have compounds that home in on the viral gp120. By grabbing onto the part that's seeking union with CD4, the drugs keep the virus from attaching. In early trials in humans, Progenics' drug successfully knocked back virus levels in the blood. One worry, however, is that the virus will mutate to resist drugs aimed at its own proteins. So another tack is "to target a host protein, which shouldn't mutate, instead of a virus protein," explains Dr. William R. Shanahan, chief medical officer of Tanox Inc. (TNOX ). His company is developing an antibody that sticks to the CD4 receptor. If all the docking ports on the cell surface are occupied with the drug, then HIV can't find a place to dock. So far, Tanox' drug hasn't had the problem that has bedeviled other efforts to block the CD4 receptor: side effects. CD4 is so important to normal human functioning that covering it with a drug could harm the cells' vital immune system role. But the other key receptor, CCR5, doesn't have this problem. Indeed, people who have naturally defective CCR5 receptors appear healthy -- and they are resistant both to HIV infection and to developing AIDS if infected. As a target for drugs, CCR5 "has been validated by nature's own experiment," says Dr. Gregory Reyes, vice-president of Schering-Plough Corp.'s (SGP ) research institute. Schering-Plough started human trials several years ago with a CCR5 blocker named SCH-C. "Viral levels dropped after only 10 days of dosing," says Reyes. "That was very exciting." Unfortunately, the drug also caused glitches in heart rhythms at high doses. So Schering has switched to another compound, dubbed SCH-D, which is more potent in the test tube and doesn't have the side effect. Clinical data are expected to show big drops in viral levels in patients. Additional promising results are coming from Pfizer Inc.'s (PFE ) CCR5 blocker, UK 427-857. In an initial 10-day trial, "we've shown a 10- to 100-fold drop in viral load," says Dr. Stephen Felstead, the company's vice-president of clinical research. Meanwhile, Progenics and Human Genome Sciences are testing antibodies -- large biological molecules -- against CCR5, rather than the small chemicals that the big drugmakers are developing. The antibodies must be injected, but one dose may last for several weeks, explains Craig A. Rosen, research & development chief at HGS. There is another ingenious way to hamper the virus' entry into cells: bollixing up the gp41 harpoon after the virus is docked. That's the tack taken by Trimeris Inc. (TRMS ) and Roche Group (RHHVF ) with their drug Fuzeon, which won Food & Drug Administration approval in March. The drug does reduce viral levels, though it's difficult to make and must be injected twice a day. Trimeris is now testing a second-generation version. There's no guarantee, of course, that any of the experimental drugs will become blockbusters. Developing medicines for AIDS is especially difficult because any new drug will be used in combination with existing treatments. That means companies must test their candidates to ensure there are no worrisome interactions when used as part of a cocktail. Pfizer, for instance, is waiting for the results of such studies on its CCR5 blocker. "We just want to make sure before we commit to a big program," explains Felstead. Still, AIDS experts believe that these hurdles will be leapt and that potent weapons against HIV are coming soon. "I think entry inhibitors could become the future of HIV treatment," says Dr. Robert R. Redfield, co-founder of the Institute of Human Virology. And if they're not enough, researchers have other ideas for attacking the virus. One is to block an enzyme, integrase, that HIV uses to slip its genes into the target cell's DNA. The battles will continue, but researchers are convinced they are gaining an advantage in the war against this tiny microbe.  By John Carey in Washington
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