Wall Street Journal - Thursday, 23 January 1997.
Michael Waldholz, Staff Reporter of The Wall Street Journal

"It's like the angel of death was told to pass me by," says Mr. Kronberg, a 51-year-old computer technician at the University of California, Berkeley. It bewilders him because, in the early years of the epidemic, he was exposed to plenty of HIV-infected people who didn't make it. Two years ago he attended a conference of Holocaust survivors. "Like them, I've wondered -- why me?"

Scientists have wondered, too. After years of study, they have made a series of discoveries showing that a small slice of the population carries a genetic quirk that renders them immune to HIV, the virus that causes AIDS. Now the race is on to develop new drugs that mimic the inborn protection that nature has given to Mr. Kronberg and others like him.

"It gives real hope for designing totally new therapies against HIV," says David Baltimore, a Nobel laureate and Massachusetts Institute of Technology scientist.

That's the good news.

The bad news is that turning this new lead and several others into marketable medicines could take a decade or more. AIDS experts worry that a public-health disaster looms in the meantime.

New "protease inhibitor" drugs, when combined in a "cocktail" with older medications, have driven the virus down to undetectable levels in thousands of people. Indeed, new studies coming out this week will show that the cocktails' use is sharply reducing AIDS-related hospitalizations and deaths. But that isn't nearly enough. AIDS is spreading most swiftly among the poor, but many of these patients may never get access to the new therapy, which costs $12,000 a year or more. Moreover, some protease patients already are developing resistance to the new therapy.

"If we don't get the next generation of drugs soon, we are going to be facing a terrible crisis," says Margaret Fischl, who directs an inner-city AIDS clinic at Jackson Memorial Hospital in Miami and oversees HIV research at the University of Miami's School of Medicine. She estimates that up to 75% of the patients at her clinic can't benefit from the new cocktails because they already have developed resistance to older medicines in the regimen. "For these people, we are going to be in big trouble soon," she says. "It's unclear what we can give them next."

The problem is that after protease, scientists have virtually nothing else. Protease inhibitors, which thwart HIV by blocking the protease enzyme that is key to a late stage of viral reproduction, were a remarkable exception in a litany of disappointment. Researchers have tried, but failed, to block myriad other enzymes crucial to HIV's ability to replicate itself.

"We've really gotten nowhere as an industry" in developing even prototype drugs that could attack these other targets, says Emilio Emini, who directs AIDS research at Merck & Co., of Whitehouse Station, N.J.

So researchers around the world are, by necessity, racing to create better versions of protease drugs and to unlock more details of the secrets of natural immunity, which have emerged only in recent months. "We are under tremendous pressure to make the leap to the next generation" of drugs, Dr. Emini says. "But that's not going to be easy. Don't even ask me when it will happen."

Dr. Emini is one of hundreds of researchers from industry and academia gathering today in Washington, D.C., to report on the impact of the new drug cocktails and their benefits as well as their limits.

While researchers in Washington bask in recent advances, at Glaxo Wellcome PLC's vast research complex in Research Triangle Park, N.C., chemists wrestle with the difficult challenge of coming up with a significant advance over the current therapies. Glaxo Wellcome currently markets two older drugs that are integral components of the new cocktails, AZT and 3TC. Although it hopes to introduce a new protease inhibitor, GW141, by early next year, scientists back in the lab are searching for something better.

Three protease drugs have been introduced in the past year, while GW141 and a drug from Agouron Pharmaceuticals Inc., La Jolla, Calif., are in final stages of testing. Now the goal is to create drugs that are easier to make and easier to take. The GW141 drug could provide some advantages over earlier protease inhibitors, such as the ability to attack HIV in the brain, but it will be marred by some of the same problems. Patients must swallow many pills on a rigid schedule every day, and the cost will be just about as high.

Most disturbing, some AIDS doctors fear that even before GW141 hits the market, some patients already may have acquired resistance to it because they have fared poorly with already-available protease cocktails.

"Our job is pretty clear: We have to produce a drug that's a significant advance over 141 and the other protease drugs already on the market," says Eric Furfine, Glaxo's protease project leader. His team is looking for a wonder drug that can be better in nine separate characteristics, such as manufacturing cost, higher potency at lower doses and better absorption in the body.

They search for answers by staring for eye-numbing hours at three-dimensional images of HIV's protease enzyme and computer models of its interaction with drugs. In what looks like a more sophisticated version of a child's tinker-toy construction, a color computer screen shows the GW141 drug locked in a biochemical embrace with HIV's protease enzyme. Jammed together with the drug molecule, the enzyme is inactivated and the virus doesn't reproduce.

Dr. Furfine's task is to produce a drug molecule that binds as snugly to the protease enzyme but is chemically sleeker -- tinier so that it can be simpler to make and so that the body absorbs it more easily, requiring fewer pills per dose. But it also must have a chemical structure that can avoid the resistance problems that one day will most likely make GW141 and other protease drugs obsolete for many people. So far, fiddling with one part of GW141's complex chemical structure almost always causes problems elsewhere in its activity.

Down the hall, Michael Luther, 40, leads an even more daunting search; hoping to create a drug to copy the rare, inborn immunity identified this past summer. "Right now, I've been given two years to find a candidate drug," says Dr. Luther, a biochemist. "We know what we're looking for. We just don't know how or when we're going to find it."

In this pursuit, he is competing or collaborating with some of the world's most acclaimed AIDS researchers. "This field is so hot right now that every new idea I have probably just occurred to 10 other people," he says. He started on the project 18 months ago, teaming up with Jay Levy, a researcher at the University of California, San Francisco. Dr. Levy had argued for years, amid widespread doubt, that AIDS progresses more slowly in some people because they carry high levels of some unknown factor that grants them natural protection. Isolate this mysterious factor and new therapies could emerge, Dr. Levy believed.

In the fall of 1995 the Glaxo team heard a compelling rumor: The elusive natural-protection factor had been found by scientists at the National Cancer Institute working with Robert Gallo, the co-discoverer of HIV. It was said to involve three specific chemicals produced in the body, part of a class of hormone-like substances called chemokines.

Dr. Gallo reported the findings three months later: In test-tube experiments, the three chemokines had effectively blocked HIV from slipping into human T-cells, the immune system's defense force and HIV's main point of attack. He believes the chemokines themselves may prove to be useful drugs, or that perhaps a vaccine could be developed that triggers the production of a squall of chemokines in uninfected patients.

Glaxo's Dr. Luther and other researchers are skeptical of such an approach, but they found the chemokine connection galvanizing nonetheless. In recent years scientists had found that these substances normally signal danger to the immune system, latching on to T-cells and directing them to the site of an infection, much like a traffic cop pointing firefighters to a fire. But it also had been found that excessive production of chemokines could cause asthma, arthritis and several other severe inflammatory diseases.

"Nobody had thought that chemokines might also play a role in AIDS," says William Coster, a top research executive at New York-based Bristol-Myers Squibb Co., which had been researching how excess chemokines can clog coronary arteries.

Boosting a patient's chemokine level to fight AIDS, therefore, would be an unworkable approach. But the finding presented a tantalizing possibility: Since chemokines thwarted HIV in the test tube, the hormone-like chemicals must be locking onto human cells at a secret doorway where HIV usually comes knocking. Now the search was on for this chemokine doorway -- the "protein receptor" on T-cells where the chemokines link up. Scientists hoped that if they could locate this receptor, they might be able to create drugs that can block it, thereby keeping out HIV.

At about the same time, a second major clue emerged from the labs at the National Institute of Allergy and Infectious Diseases, where experts had spent years searching for unknown doorways by which HIV enters healthy cells. In the late 1980s HIV's first entryway was discovered: The virus first locks onto a surface sector of the target cell known as CD4. But simply plugging the CD4 opening had failed to stop HIV from spreading, and so researchers realized the virus must also use a second doorway into human cells.

"For 10 years my labs were searching for it, without luck," says Edward Berger, a researcher at NIAID. Finally last year, his team found an alternate entry point, a gateway molecule they dubbed "fusin" because it lets HIV "fuse" itself into healthy cells. But what especially startled Dr. Berger was that his fusin gateway was precisely where Dr. Gallo's chemokines hook up to T-cells to block HIV.

"It was a remarkable coincidence of findings," Dr. Berger says.

When he discussed his work at a scientific gathering in Santa Fe, N.M., last February, "all hell broke loose," says Thomas Doms, a virologist at the University of Pennsylvania. But when other researchers examined fusin, they quickly realized that it was used by only one of the two most common types of HIV, the late-stage virus that exists mainly in patients with advanced forms of AIDS. The other kind of HIV, the early-stage virus that is passed from person to person, doesn't bind itself to the fusin gateway.

That meant there had to exist still another gateway molecule separate from fusin, but remarkably similar in its chemical design. "An incredible race" ensued to find this third secret doorway, Dr. Doms says.

By June it had been located. Leveraging off the new knowledge about chemokines, Dr. Doms's lab and four others all reported in the same week that they had discovered a chemokine receptor on the surface of T-cells. This receptor, soon dubbed CCR5 (for chemokine receptor 5), was the site where HIV is able to force its way in, taking control of the reproduction machinery of healthy cells to churn out new copies of HIV.

"Starting then, our goal was to find a drug to block CCR5," says Dr. Luther at Glaxo, whose lab identified CCR5's existence at about the same time. Drug makers were keenly interested because this offers familiar terrain; about 40% of all common drugs, such as ulcer and heart remedies, work by blocking cell receptors that are structurally similar to CCR5.

Ordinarily researchers would take a finding like this and begin animal tests to learn whether it might work in humans. But nature had given the drug companies ready-made proof: the mystery of AIDS-immune survivors.

At the Aaron Diamond AIDS Research Center in New York, Richard Koup had been studying 25 people who had staved off HIV infection despite repeated exposures. Upon hearing that CCR5 had been identified, he began examining the protein in the blood of these subjects. He found that three of them carried "defective" versions of CCR5 as a result of inheriting a mutation in the gene that produces this protein.

How the rest of the group has gone uninfected is unknown, but "the extraordinary thing to us was that this inherited gene mutation blocked HIV, but that the subjects were otherwise healthy," Dr. Koup says. Dr. Luther of Glaxo adds: "Nature had given us the kind of perfect experiment you look for when searching for a new kind of drug. In these people, we had evidence that if you blocked CCR5, you blocked infection but caused no other harm. That's the criteria of effectiveness and safety you look for in a drug."

In San Francisco, researchers who had been puzzling over the immunity of Frank Kronberg ran a similar test and finally had their answer: He, too, had inherited the defective CCR5 gene. Now his blood samples are under study at several research labs that hope to identify new drugs that mimic this defect.

National Institutes of Health researcher Stephen O'Brien estimates that perhaps 1% of the white population carries this inborn protective mutation. Scientists hypothesize that the gene defect gained a stronghold in the population centuries ago because it provided protection against some previous unknown viral epidemic. A small portion of the black population displays AIDS immunity, too -- yet the CCR5 defect hasn't been found, indicating that something entirely different is at work.

These days, Dr. Luther's team and rivals are screening hundreds of thousands of chemicals. They use 'round-the-clock robotic assembly lines to monitor test-tube reactions in the hopes that one substance, by binding to the CCR5 receptor, could keep HIV at bay. This would provide the chemical lead they need to start designing such a drug.

But researchers caution that it typically takes 10 years for a new insight in human biology to yield a new kind of drug. In addition, even if they succeed in blocking the CCR5 doorway, HIV may use yet another point of entry that has yet to be discovered. That wouldn't be surprising, say scientists who have been consistently awed by the adaptability of their viral adversary. "We're witnessing a remarkable story," but success will require "a great deal of serendipity," Dr. Luther says. "There's no way to figure how this will end."

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