Attacking HIV Every Which Way


While it's true that the crafty AIDS virus is rapidly developing resistance to today's arsenal of powerful drugs, the good news is that drug companies may be able to stay a step ahead of it.

One promising new drug candidate is from Tibotec in Rockville, Md. Company scientists set out to understand how the virus can change to elude current so-called protease inhibitor drugs, which work by blocking the action of the enzyme protease, which the virus needs to copy itself. But the virus can subtly change the shape of the enzyme, preventing the drugs from sticking tightly enough to block its action.

Tibotec scientists tackled the problem by first figuring out the three-dimensional shapes of each of the protease enzymes used by various strains of HIV. Then they began screening for drugs that could still bind to the enzymes, no matter what their shape. As Tibotec's John Erickson reported on Feb. 5 at the 8th Annual Conference on Retroviruses in Chicago, the effort has born fruit. The company has created one drug that works, in the petri dish at least, against all the resistant strains of HIV. "It has an extraordinary capacity to block multidrug-resistant strains in vitro," says Erickson.

FOLLOW THE LEADER. How does the drug, dubbed TMC126, work? For one thing, it binds very tightly to the key site on the protease enzyme. But more important, it retains a certain amount of flexibility, so as the virus changes the shape of its enzyme, TMC126 can follow suit and still bind just as tightly. Erickson cautions that the drug "is still in the early stages of development." Tibotec has just begun the first small study in humans. But so far, there's no evidence for toxicity that might keep the drug from being a viable treatment, he says.

Encouraging progress is also coming in an entirely new class of drugs. The existing treatments fight HIV once it has already infected cells by inhibiting protease or another enzyme, reverse transcriptase, and preventing the virus from replicating.

But another way to tackle HIV is to prevent it from getting into the cell in the first place. In a series of remarkable recent studies, researchers have been able not only to uncover the complex molecular dance HIV performs to breach a cell's defenses but to devise ways to bar the door.

HARPOONED. Here's what happens: As HIV approaches a vulnerable T-cell, it first attaches to a receptor on the surface of the cell known as CD4. That causes a change in the shape of the protein that surrounds the virus like an envelope, exposing another binding site. That newly exposed piece of the virus latches onto another receptor on the cell surface called CCR5.

That's when the action really begins. The second binding triggers a far larger change in the shape of the virus's outer envelope, unleashing the protein gp41. This protein shoots out like a harpoon, spearing the cell membrane, and then coils back on itself, pulling the virus down to the cell surface. That allows the two membranes to fuse, releasing the deadly viral genes into the cell.

After CCR5 was discovered in 1996, a Schering-Plough team led by Bahige M. Baroudy immediately launched an effort to develop a drug that would attach to the receptor and prevent this cascade of events. Just a little more than four years later, Schering Plough scientists will report on Feb. 7 the first results from clinical trials.

"EUREKA!" Further along is a drug by Trimeris that works by defeating the harpoon itself. Its story began in the early '90s, when Tom Matthews, then a researcher at Duke University, was trying to develop a vaccine. The idea was that bits of gp41 could be used to prod the immune system into making antibodies against it, which could then block viral entry. The idea flopped. But Matthews, almost as an afterthought, tested a piece of gp41 to see if it could inhibit the virus in the test tube. To his surprise, it did. "It was a eureka moment," recalls colleague Dani Bolognesi. "Tom came running up the stairs and said he'd never seen anything like this before."

The researchers figured out the piece of gp41 worked by attaching to the virus' own gp41. Trimeris, the company Bolognesi and Matthews founded in 1993, and partner Hoffman-La Roche have shown the substance, T-20, successfully fights the virus in patients without causing the debilitating side effects of today's drug regimens.

At the Retrovirus meeting, Trimeris reported especially encouraging new results. (The company is trying to get the drug to market quickly by testing it as a last-resort therapy for people for whom all other drugs have failed.) But in the new study, the company added T-20 to a powerful four-drug regimen that was already working well at keeping virus levels low. The result: Viral levels dropped by an additional factor of 10. "We were surprised to see an effect over and above this powerful background treatment," says Bolognesi, Trimeris' CEO.

FAST FLU. Other new studies show it may be a quirk of nature that allows T-20 and other so-called fusion inhibitors work as well as they do. The key is it takes a relatively long time for HIV to bind to the two cell receptors and unleash its harpoon. As a result, T-20 has time to sneak in and bollix up the works. In contrast, other viruses that use a similar harpoon mechanism to get into cells operate much more swiftly. A fusion inhibitor "wouldn't work on flu because it happens too fast," explains Robert Doms of the University of Pennsylvania.

But that raises an intriguing possibility: "Can we slow HIV down more to make these compounds more potent?" Doms asks. The answer seems to be yes. One way to do it is to combine two types of inhibitors. Using a drug like Schering-Plough's CCR5-blocking compound inhibits the virus enough to make the harpoon inhibitors like T-20 10 times more effective.

If these new drugs continue to show promise in clinical trials, it soon may be possible to hit the virus from so many different fronts, both inside and outside the cell, that HIV doesn't stand a chance. By John Carey in Chicago


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