Protease inhibitors -- the ungrim reapers The DNA that the AIDS virus has inserted into the nucleus has only one job: to make fresh viral RNA. After that, the new RNA leaves the nucleus and enters the cytoplasm. At that point, there's just one detail to be attended to before the new viral RNA is ready to exit the cell and become a new particle of virus: The proteins surrounding the viral RNA that make up the structure of the virus particle must be cut to the proper length.

As the new viral RNA prepares to leave the cell, its proteins must be cut to length by enzymes called proteases. Protease inhibitors interfere with this step. Immune system cell illustrations © George Eade. The chopping job falls to yet another enzyme, called a protease. And like the enzymes we've already seen, this enzyme offers another chance to attack the virus.

Scientists have known this for years, during which time they've struggled to make protease inhibitors a real drug that could be taken orally and be free of severe side effects. Since being introduced into the market in December, 1995, the protease inhibitors have become the champions of the war on HIV. Protease inhibitors are usually used in combination with two reverse transcriptase inhibitors in what is called "triple-drug-" or "combination drug therapy." This multi-pronged attack has finally started turning the corner in the war on HIV. In 80 to 90 percent of patients, it reduces the viral load to undetectable levels and restores health to people who have been gravely ill. The use of several drugs to combat one infection is not new: Studies have proven that the technique works in treating cancer and tuberculosis. Until recently, the problem in applying this approach to AIDS has been that there were not many drugs to use in combination. Since the first protease inhibitor was approved in December, 1995, two more have reached the market. Here are research results showing that combination treatment with a protease inhibitors can delay HIV disease progression and death. Here's a stunningly complete assessment of current AIDS drugs, published in March, 1997. Almost a miracle cure If you ask the many patients whose health protease inhibitors have restored, the drugs must seem like miracle cures. Except they're not actually cures. The advances in treatment are "justly heralded," says University of Maryland AIDS researcher Robert Gallo, but it's "dangerous if you start talking about cures." For one thing, he says, between 10 and 20 percent of patients just can't tolerate their side effects, which include nausea, diarrhea and numbness. Furthermore, although the virus is absent from the blood, it could be lurking in other tissues, Gallo maintains. Gallo, a virologist, says it's too soon to say AIDS has been cured until a patient dies from another cause, and an analysis of tissues shows no genetic sequences of the virus. Despite the extraordinary success of triple-drug therapy, Gallo points out that the few patients who have been taken off the drugs have relapsed. That, he says, proves that HIV is dormant, not absent. And any amount of HIV lingering in the body makes people nervous -- since it is a wily foe, with an immense ability to mutate and defeat the immune system. There's another small problem: These therapies are extremely expensive. "I don't think we can make this work for approximately 99 percent of the people who need it around the world," Gallo says. (Protease inhibitors have had a fringe benefit: they seem also to inhibit the reproduction of some deadly hepatitis viruses.) Gallo insists that what is needed is a vaccine -- something that can prevent the initial infection. And while vaccine research has been one of the most frustrating parts of the whole AIDS story, some new discoveries about how HIV actually enters immune cells may change that equation. If you've already read our chemokine story, can we interest you in the credits or our bibliography?

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