He Wants to Test a 'Cure,'
But Others Are Critical;
A Talent for Sound Bites
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Irene Diamond's Dream Lab

NEW YORK -- Twenty-one men infected with the AIDS virus -- test subjects in a controversial experiment -- have been able to stave off illness for the past year by gulping down about 20 pills a day. Now researchers are asking them to do the unthinkable: halt the multidrug "cocktail" regimen that has quelled the growth of the deadly virus inside them.

It is an audacious gamble. But lead researcher David Ho argues it is the only way to test whether the cocktail approach, which has boosted the health of thousands of patients this year, could become an outright cure for AIDS if used early and intensively enough. So far, though, none of the patients have agreed to stop treatment.

"Would you?" asks Scott, a health-care worker and test subject who refused researchers' request two weeks ago. Scott has gone almost a year without any sign of the virus in his bloodstream, but he frets: "I think the virus is probably still in there somewhere, waiting. Someone else is going to have to go first."

Some rival scientists say Dr. Ho's bold gambit amounts to scientific grandstanding, a tactic to generate publicity for himself and raise funding for the laboratory he runs, the Aaron Diamond AIDS Research Center. Critics worry that Dr. Ho's experiment, in addition to possibly endangering his patients, will falsely raise hopes.

"It's going to mislead people into thinking there is a cure," says Mark Harrington, a veteran patient advocate with the New York-based Treatment Action Group. "And, of course, that's crazy." A skeptical Robert Gallo, the co-discoverer of the AIDS virus and director of a rival research center in Baltimore, bluntly asks: "Why are there so many press releases" emanating from Dr. Ho's lab?

Dr. Ho rejects such criticism. He says he avoids using the word "cure" because "it's way too premature." But he argues: "We are asking critical questions that need to be asked, pushing the virus as hard as we can, probably harder than anyone else. . . . We want to find out what's achievable, and the only way to conduct this kind of experiment is in people. And that creates all sorts of commotion.

"People say I'm a news hound," adds Dr. Ho, who has been cited in several hundred articles during the past two years, "but it's actually making it harder for me to get my work done."

The star researcher has, however, developed an undeniable knack for the easy-to-swallow soundbite. While other scientists typically wait to discuss their work until after publishing the results in scholarly journals, Dr. Ho this year has grabbed headlines by making bold claims at scientific conferences months before publishing his findings. Recently he has, in so many words, predicted how long it may take for the virus in some patients to be completely eradicated: perhaps after six months to three years of cocktail therapy, if treatment begins soon after infection.

"It's mostly speculation right now," counters Jerome Groopman, an AIDS researcher at Beth Israel Deaconness Medical Center in Boston, who cites a dearth of hard evidence supporting such lofty speculation. Like others, he wonders about the ethics of asking the patients doing well on the drugs to stop therapy. "We don't know enough right now to predict how long we'll have to treat them," Dr. Groopman says.

The Diamond Center has been the object of much acclaim this year -- as well as criticism and jealousy -- for discovering important new details about the behavior of the AIDS virus and promoting a new class of drugs known as protease inhibitors. Founded just six years ago, the lab has rapidly become one of the world's foremost AIDS research institutes.

It is the passion of a most unlikely duo: Dr. Ho, 43 years old, a subdued yet disarmingly self-assured scientist born in Taiwan and schooled in California; and his wealthy New York benefactor, Irene Diamond, an 86-year-old widow who has spent the past 10 years in a late-life odyssey "to make a real difference," as she puts it.

Mrs. Diamond was a script reader on some of Hollywood's most famous movies in the 1940s and '50s, working for producer Hal Wallis, whose credits include "Casablanca." In 1942 she married Aaron Diamond, who later built a fortune as a New York real-estate developer. In 1984, while they were vacationing in Florida, her husband broached the idea of placing $150 million of assets into a foundation to support the arts, medicine and minority education in New York. One day later, Aaron Diamond died of a heart attack.

"I was determined to carry out his dream," Mrs. Diamond says.

Thus the Aaron Diamond Foundation was endowed in 1986. In 1990 it created the Aaron Diamond AIDS Research Center, donating $11 million, matched by a city contribution of $3.4 million, to set up the lab in an abandoned floor of an old public-health building. Some of the world's most acclaimed AIDS scientists applied for the top job. Against the advice of some prominent medical experts, Mrs. Diamond chose a relative unknown -- David Ho.

"I didn't want a diva, a prima donna," she says. "I wanted someone young and ambitious, with new ideas. Once I met David, I knew we had our man."

Flush with cash, Dr. Ho outfitted the new research center with expensive, state-of-the-art equipment and lured away leading scientists from bigger-name labs. Soon, it will have to survive financially on its own. On Dec. 31, Mrs. Diamond plans to shut down the Aaron Diamond Foundation because it will have finished handing out all of the wealth that she and her husband had set aside for good causes. Attracting funds from other sources to keep the center financially stable, critics argue, is one motive behind Dr. Ho's propensity for publicity.

Still, Dr. Ho and his team have earned justifiable accolades for challenging long-held assumptions about how the AIDS virus works and, by inference, how it can be controlled. "David's work in the past few years has helped to completely transform our understanding of HIV," says Joep Lange, a leading AIDS researcher at the University of Amsterdam. "It is one of the most important contributions of the past decade."

For most of the past 15 years, researchers and doctors believed that after an initial infection, the virus goes into hiding, lying dormant for years before reawakening and ravaging a patient's disease-fighting immune system. So any drugs for attacking HIV, the AIDS virus, were withheld until a patient developed visible symptoms of full-blown AIDS, usually three to eight years after infection. That way, researchers argued, HIV had less time to spin off new copies that were resistant to the therapy.

But Dr. Ho had believed, for years before he could actually produce any proof, that HIV didn't sit idle at all, but instead started reproducing itself in massive quantities almost immediately. This implied such a significant reversal in long-held precepts of AIDS research and treatment that, for several years, Dr. Ho couldn't raise federal grant money to explore his theory; backed by the Diamond Center, he was able to pursue his hunch.

Dr. Ho and his team published a startling set of findings in support of his theory early last year. They found that the virus is a constant dynamo of activity from the first moment of infection, reproducing perhaps a billion copies every day. These offspring wage a nonstop, ferocious battle against the immune system, eventually overwhelming it. Waiting years to begin attacking HIV, Dr. Ho now asserts, can put the patient too far behind to ever fully recover.

Then Dr. Ho galvanized the AIDS community with a more disturbing disclosure in January of this year. At a crowded science meeting in Washington, D.C., he revealed, in advance of publication, new findings showing that the virus's rapid growth rate was 10 times as great as estimated a year earlier. By analyzing test patients' blood every few hours instead of just every few days, he discovered that the rampaging virus produces an unfathomable 10 billion to 30 billion viral offspring every day.

That meant that new mutant copies of HIV, some of them possibly drug resistant, were being produced every few minutes -- and that the only chance of subduing the virus was a combination of several drugs attacking different parts of the virus, all at once. At the same session, Diamond researchers reported preliminary findings showing that a three-drug attack had shut down 99.9% of this rampant viral presence in the blood of test patients, something never accomplished before.

Since then, Dr. Ho has become evangelical in arguing that the drug cocktails should be used much more aggressively and earlier than ever before. That stance rankles many colleagues, who say such early use of the complicated and costly new medicines is impractical, unaffordable and just plain risky. Early and wider use of the drugs, health-policy experts warn, would require already-strapped federal and state programs to spend an additional $5 billion a year. Broader distribution also could hasten the emergence of HIV strains resistant to the newest drugs, allowing them to spread.

"That's a pretty frightening concern," says Eve Slater, a clinical-research executive at Merck & Co., which developed and markets one of the powerful new protease inhibitors. "The drugs we have now have to last as long as possible, because we really don't know when we'll develop new drugs to replace them."

By now Dr. Ho has become accustomed to getting caught in the crossfire. His outward style -- soft-spoken and unfailingly polite -- masks an aggressive maverick streak. At recent AIDS conferences, he has been accorded celebrity status, yet "he is one of the nicest guys you'll meet in the high-pressure field of competitive science," says Henry Chang, a researcher at Healthcare Foundation of Los Angeles who worked for Dr. Ho in the late 1980s.

Dr. Ho came to America from Taiwan at age 12, arriving in Los Angeles with his mother and a younger brother to join his father, who had immigrated to the U.S. several years earlier to study electrical engineering. Although he couldn't yet speak English, young David soon excelled in school, especially in math and science. He attended the California Institute of Technology and earned a medical degree at the University of California at Los Angeles.

As a young doctor training at a Los Angeles hospital in 1981, he began treating some of the first patients in the U.S. complaining of strange skin cancers and unusual infections. Many experts believed the problems were caused by hard living -- too much sex and drugs -- but Dr. Ho believed otherwise.

"From the start I thought some type of infectious agent, maybe a virus, was at work," he recalls. He was eager "to try to figure out what was going on."

In 1982 he headed east to Harvard University, joining Martin Hirsch, a leading virologist at Massachusetts General Hospital and Harvard School of Medicine, who was trying to track down the cause of the strange symptoms. About a year later, scientists in France and the U.S. isolated HIV.

Most early research efforts were aimed at looking for a vaccine and finding new treatments. Dr. Ho, drawing on his training as a doctor instead of just as a biologist, wanted to understand the enemy -- where it lurks, how it behaves. He therefore embarked on a prodigious portfolio of experiments aimed at unraveling how the newly discovered virus works.

He was the first, for instance, to isolate HIV in semen, proving that it could be transmitted sexually; and he proved it wasn't active in saliva, indicating it couldn't be transmitted in a kiss. He also found the virus in spinal fluid, indicating it endangered the central nervous system and the brain.

"David was asking the kind of questions that made you say, `Gee, why didn't I ask that?'" says Harvard's Dr. Hirsch. "From his earliest days as a researcher in my laboratory, David has consistently shown a unique ability to cut to the heart of the chase, to solve difficult problems in a simple and elegant way."

Dr. Ho left Harvard in 1986 to run a laboratory at UCLA, continuing his research. A few years later, he helped expose one of the first major failures in AIDS treatment, involving a genetically engineered protein called CD4. But in failure he found hope, figuring the flop had to be caused by HIV's heretofore unrecognized reproductive prowess.

"CD4's failure led some of us to believe the amount of virus circulating [in the body] must be much greater than previously thought," he says. Only by gaining new insight into how aggressively HIV spreads through the body "could we ever hope to come up with a rational treatment. But that kind of research required more resources than I had" at UCLA.

When word spread in 1990 about the plum research job up for grabs at the New York's first and only AIDS research lab, Dr. Ho joined a lengthy list of applicants. He won the top job by presenting his interviewers with an unusually clear goal: He wanted to quantify the precise size of the viral attack and test ways to subdue it. "I couldn't believe my good fortune," he says, adding, "Irene has been supportive, inspiring and very generous. If this place is unique, it's because of her."

Most young scientists scrape by on elusive funding from federal grants or drug companies and work in university labs where resources are scarce, offices are cramped and staffing depends on grant renewals. To the envy of rivals, the Diamond Center started out with ample seed money to hire talent, acquire new gear and begin research that would help secure grants later on.

Developers gutted and rebuilt the lab, housed on the seventh floor of a city-owned building across First Avenue from New York's famed Bellevue Hospital. The Diamond Center has dark tiled floors and hallways lined in blond oak paneling illuminated by frosted-glass sconces. Nine shiny, spacious labs hold specially designed virus-containment units and advanced genetics equipment; benches and walls glisten with stainless steel.

Last month, the center opened a second floor of lab space, conference rooms and offices, courtesy of a new $10 million grant from Mrs. Diamond's foundation. She also has given the AIDS lab real-estate assets worth another $5 million, which eventually will be sold.

"The place is very impressive looking," says Richard Koup, an infectious-disease researcher who was Dr. Ho's first hire at Diamond. "It helps us recruit good people. It shows them right away that this place is different." David Baltimore, a Nobel Prize laureate at the Massachusetts Institute of Technology, adds: "A major reason for David's success is that he's put together a group of very solid scientists, about the best group you'll see anywhere. No other AIDS lab can boast so many accomplished people."

Dr. Koup, for example, has pursued work that many researchers believe may contribute to developing the next generation of AIDS drugs, perhaps even a preventive vaccine. For almost two years, he had been monitoring a small group of New York subjects who claimed they had been repeatedly exposed to HIV but for some strange reason weren't infected. Something about their biology must be different. Identify it, and it could become a new weapon, scientists figured.

Then last spring, several rival research groups reported that they had identified an important chemical gateway in immune-system cells that acts as an entryway for HIV. Dr. Koup immediately examined that chemical in the blood of his AIDS-defying subjects. In August, he reported a surprise: These people had an inborn defect in the entryway chemical that protected them from getting infected. Several giant drug companies are racing to discover drugs that can mimic that lifesaving defect.

"There's no way I could have done this work at a university lab," Dr. Koup says; the collection of top-notch researchers at Diamond was the key. "When I need a solution, a lab technique or insight I just walk across the hallway. We have a critical mass here."

That critical mass similarly contributed to Dr. Ho's much-hailed findings about the surprisingly prodigious reproductive power of the AIDS virus. (Although he got most of the credit, a team at the University of Alabama at Birmingham had made a similar discovery.)

The Alabama team had been using a powerful drug from Merck and, when HIV overwhelmed the new remedy so quickly, concluded it must be because of the virus's particularly explosive growth. "David gets a lot of credit because he quantified what we saw, he proved what we knew," says Emilio Emini, Merck's top AIDS scientist. "If anything, his talent is for describing things better than others, and for doing the experiments others simply overlook."

And so it is that Dr. Ho, testing his early-treatment thesis, has embarked on the controversial experiment involving the 21 New York patients. All of them began the multidrug therapy within just six months of being infected. Many of the patients have gone a year without detectable virus in the blood. Although none have agreed to stop taking the drugs yet, the Diamond researchers will continue following them, asking them periodically to go off therapy. Dr. Ho hopes to prove that the drug cocktail can entirely eradicate all HIV in these patients.

Other researchers say more realistic goals should be pursued, such as discovering new targets in the virus for attack and testing which combinations of drugs work best. They note that, while doctors regularly eliminate illness-causing bacteria with antibiotics, no drug therapy has ever been able to vanquish any virus, let alone one as pernicious as HIV.

"We simply don't know enough about the virus, about whether you can reach all the places where it hides in the body," says Dr. Gallo, director of the Institute of Human Virology in Baltimore. Douglas Richman, a leading researcher at the University of California, San Diego, who is trying a limited eradication test of his own, says: "I think [Dr. Ho's] chances of success are, at best, 50-50."

Dr. Ho is betting his odds are better. Because the patients started the therapy so soon, their immune systems haven't been beaten down by the virus, and HIV hasn't had much time to turn out drug-resistant clones or to advance into the brain, spleen and other difficult-to-reach organs and tissues.

Doubters say those inaccessible "sanctuary" sites probably harbor lingering viral particles that can emerge months and years after the drug cocktail has cleared HIV from the bloodstream. But Dr. Ho argues that the virus may simply burn itself out after six months to three years of drug bombardment. He believes that the lingering HIV copies in these sanctuary sites will disappear when the cells that host them die a natural death and are replaced by new, uninfected cells.

The patients, then, would be cured.

"That's a pretty extraordinary claim," says Jay Levy, a leading virus researcher at University of California, San Francisco. "What's it based on?"

Answer: Theory and mathematics, actually, rather than hard evidence. Dr. Ho bases his prediction on a mathematical calculation that even he has trouble explaining but which is based on the speed with which virus levels in the bloodstream decay during the first few months of treatment. The only way to know for sure, however, is to follow the 21 test patients subjects and persuade some of them to drop the cocktail therapy to see what happens. In recent weeks, the Diamond center has recruited 30 patients into two additional eradication experiments, one of which uses two drugs not yet on the market that may attack virus lodged in brain tissue.

Dr. Ho and his clinical director, Martin Markowitz, argue that if HIV reappears they can resume the cocktail attack. So far, none of the patients is ready to risk it.

In coming months, the Diamond researchers will begin removing tissue from several potential sanctuary sites in the patients' bodies, searching for the presence of hidden virus. If they find that HIV has so securely inhabited these tissues, eluding even the "early and hard" attack of the protease cocktails, it will mean the virus has prevailed once again.

"Then we will know a lot more, even if what we've learned is upsetting," Dr. Ho says. He acknowledges he is feeling the pressure of the public glare and says that proceeding is like conducting "a biochemistry experiment with the whole world looking over your shoulder."

But "the only way we'll find out is to do the experiment. Only with data can we move ahead," he says. Is it possible he is wrong? "Absolutely," he allows, then adds: "I don't think I am."