THE DISEASE DETECTIVE

Dr. David Ho doesn't look like a gambler. With his boyish face and slender build, he could more easily pass for a teenager than for a 44-year-old father of three--or, for that matter, for a world-renowned scientist. In fact, when he was an undergraduate at the California Institute of Technology back in the 1970s, Ho hung around the blackjack tables in Las Vegas, tilting the odds in his favor by memorizing each card as it was played. He got so good at counting cards that he was thrown out of several casinos.

Today Ho is still something of a gambler, though in a very different field and for much bigger stakes. The director of the Aaron Diamond AIDS Research Center in New York City, he has come up with a daring strategy for flushing out the virus that causes AIDS. As he explained at the 11th International Conference on AIDS in Vancouver, Canada, last summer, Ho (like more and more doctors) is using powerful new drugs called protease inhibitors in combination with standard antiviral medications. But unlike most doctors, he gives the so-called combination therapy to patients in the first few weeks of infection.

Already the HIV in his patients' blood has dropped so low it can no longer be measured. Because he is attacking early and not waiting for full-fledged AIDS to develop, Ho told the conference, there is a good chance that within two or three years the virus could be completely eliminated.

Eliminated. Just a few months ago, no one in the AIDS community and no reputable scientist would presume to imagine such a thing. Journalists, activists and researchers peppered Ho with questions at the podium. Had he found the cure? Could people stop worrying about AIDS? Could they throw away their condoms?

No, no and no. What he had done, Ho explained, was begin an experiment that might, under the right circumstances, eliminate the virus from a small group of men caught within three months of infection. He couldn't offer the same hope to the estimated 100,000 patients in later stages of infection who in the past year have begun taking the same antiviral "cocktails"--often with encouraging results--but whose AIDS is probably too far advanced for them to expect a long-term recovery.

Like so many promising HIV treatments, Ho's strategy could fail. It could even backfire if it is mistakenly touted as a kind of "morning after" treatment that allows people to relax their guard and engage in risky sexual behavior. By desensitizing the virus to medications, it could jeopardize a patient's ability to respond to future treatments. Worse yet, it could inadvertently create a mutant strain of virus resistant to all currently available drugs--a kind of super HIV--that could lead to a second, even more devastating AIDS epidemic.

There are other problems. Even if the treatment works, it isn't practical. HIV-positive patients would have to start taking the drugs immediately after infection, before they realize they're sick. And even if the drug cocktails can be made to work in the later stages of infection, they are far too expensive to do much good for the 20 million people in the developing world who are infected with HIV. In the long run, scientists believe, only an AIDS vaccine will stop the global epidemic.

Still, it's easy to understand the tentative sense of hope and excitement that has spread across the AIDS community in the months since the Vancouver conference. Ho's speech, for all its caveats, provided the first concrete evidence that HIV is not insurmountable. After 15 years of horror, denial and disappointment, the pendulum may at long last be swinging against AIDS.

A TEAM EFFORT

David Ho would be the first to say that he cannot take all the credit. It was an immunologist from Los Angeles named Michael Gottlieb who in 1981 reported the first cases of what was then called gay pneumonia. It was the U.S. Centers for Disease Control that alerted doctors to the gathering epidemic and established that the infection was transmitted through blood transfusions, tainted needles and unprotected sex. It was Dr. Luc Montagnier's laboratory at the Pasteur Institute in Paris that first isolated the killer virus in 1983. It was Dr. Robert Gallo and his colleagues at the National Cancer Institute in Bethesda, Maryland, who made it grow in the lab, which allowed for the development of an antibody test. It was the National Institutes of Health that funded the basic research on HIV and AIDS. It was the big drug companies like Burroughs Wellcome and Merck that brought a growing list of anti-HIV drugs to market.

But Ho, working alone or in concert with others, fundamentally changed the way scientists looked at the AIDS virus. His breakthrough work in virology, beginning in the mid-1980s, revealed how HIV mounts its attack. His tenacious pursuit of the virus in the first weeks of infection helped show what the body does right in controlling HIV. His pioneering experiments with protease inhibitors helped clarify how the virus ultimately overwhelms the immune system. His work and his insights set the stage for an enormously productive shift in the treatment of AIDS away from the later stages of illness to the critical early days of infection.

Once, not so long ago, researchers believed that nothing much happened after HIV gained entry into the body. The virus simply hunkered down inside a few of the immune system's T cells--the linchpins of the body's defensive forces--for anywhere from three to 10 years. Then something, no one knew what, spurred the microbial invader to awaken. In this picture, the AIDS virus spent most of its life hibernating before starting its final, deadly assault.

In the past two years, Ho and his colleagues have demonstrated that this picture of the virus is wrong. There is no initial dormant phase of infection. Ho showed that the body and the virus are, in fact, locked in a pitched battle from the very beginning. At first many AIDS researchers found this hard to accept; it challenged some of their most cherished assumptions. If Ho was right, doctors would have to radically alter the way they treated AIDS.

It wasn't the first time that Ho had overturned conventional wisdom. During the past 15 years, he has demonstrated an uncanny ability to ask questions that seem obvious only in retrospect and to probe key issues others have overlooked. It's a trait that does not endear him to some of his rivals. A few have accused Ho of being a publicity seeker who is giving AIDS patients false hope. Upon examination, however, most of the accusations appear to spring from professional jealousy. "David is the type of individual whom I feel particularly good about when he achieves success," says Dr. George Shaw, one of Ho's strongest competitors, who runs a state-of-the-art AIDS research laboratory at the University of Alabama in Birmingham. "He is a stellar scientist."

Ho has an extraordinary knack for being in the right place at the right time. Two years after he received his M.D. from Harvard Medical School, Ho witnessed the birth of the AIDS epidemic. He remembers how baffling it seemed.

The year was 1981, and Ho was chief medical resident at Cedars Sinai Hospital in Los Angeles. Across town at UCLA, Gottlieb had identified a new syndrome that seemed to target gay men. Each of the cases was different, but all had one thing in common: whatever was making the men sick had singled out the T cells for destruction. Eventually the body's battered defenses couldn't shake off even the most innocuous microbial intruder. The men were dying from what doctors termed opportunistic infections, such as Pneumocystis pneumonia, which attacks the lungs, and toxoplasmosis, which often ravages the brain.

Ho began seeing more and more of these patients in the intensive-care units at Cedars Sinai. Some doctors thought that poppers and other recreational drugs triggered the immune collapse. Others believed it was a bizarre allergic reaction from having too many sex partners. But Ho fell into the camp that suspected a virus. He quickly decided to specialize in AIDS research. "David was clearly a big thinker even then," says Dr. Mark Ault, who was a resident at Cedars Sinai at the time. "But that didn't stop us from kidding him about how he was always looking for gay men."

Ho ignored the gibes and in 1982 landed in Martin Hirsch's virology laboratory at Massachusetts General Hospital in Boston. A prominent scientist in his own right, Hirsch is known for cultivating talented young researchers.

Like many other ambitious young scientists, Ho wanted to be the first to isolate the virus that causes AIDS. Luc Montagnier and Robert Gallo beat him to it. (Ho came in fourth, after Jay Levy of the University of California, San Francisco.) Still, while working in Hirsch's lab, Ho became expert at detecting HIV in places where few were able to find it. He was the first to show that it grows in long-lived immune cells called macrophages and among the first to isolate it in the nervous system and semen. Just as important, he showed that there isn't enough active virus in saliva for kissing to transmit the infection. "David had the Midas touch," Hirsch recalls. "Whatever he did worked."

Unfortunately, Hirsch was not Midas, and he couldn't afford to pay his postdocs more than the standard $18,000 yearly stipend. To support his family, Ho started moonlighting in Mass General's walk-in clinics. It turned out to be the right time to be in that place too. "The clinics are where you see the flus, the colds, the common illnesses," Ho says. In the mid-1980s, however, he started seeing gay men with what appeared to be an unusually severe flu. They always got over their illness without any of the hallmarks of AIDS. Still, he wondered, could there be a connection? Could these flu-like ailments be the signs of the men's very first exposure to HIV?

Sure enough, blood tests showed that the "flu" corresponded with the sudden appearance of HIV--and the total absence of any influenza viruses. Then, after a few weeks, the antibodies in the immune system would jump sharply while HIV disappeared from the circulation. It was the first evidence that HIV triggered an active infection. But not even Ho would recognize its significance until years later.

LEARNING FROM FAILURE

Despite rising casualties, Washington kept tight purse strings on funding for AIDS research for much of the 1980s. By 1987, though, even Ronald Reagan knew that AIDS was a serious threat. The plague had encircled the globe, stretching from Africa to Asia. The antibody test revealed the presence of HIV in the blood supplies of the U.S., France and Japan. The FDA approved use of the antiviral drug AZT in a record 14 weeks.

At that time, scientists across the U.S. were excited about a possible breakthrough treatment: soluble CD4. They knew that HIV does not infect T cells at random. It must first attach itself to a particular protein, called CD4, on the T cells' surface. Perhaps, researchers reasoned, if they flooded the bloodstream with free-floating CD4 molecules, the molecules would act as decoys and prevent HIV from infecting the T cells. Preliminary tests on viral samples grown under laboratory conditions showed that soluble CD4 worked beautifully.

Ho had taken a junior faculty position at UCLA and moved his family back to California. He contacted Dr. Robert Schooley of the University of Colorado Medical Center in Denver, and together they embarked on a clinical trial of soluble CD4 in two dozen patients, many of them in the later stages of AIDS. Unfortunately, Ho and Schooley wound up proving that soluble CD4 doesn't work. In the process, however, they discovered something very interesting--that there were tens of thousands of infectious viral particles in their patients' bodies, a lot more than anyone had expected.

It took Ho only a few weeks to figure out why soluble CD4 didn't work. The early tests on the treatment were done on weak strains of virus grown in the lab. Somehow wild viruses could tell which CD4 molecules were decoys. Ho and the rest of the AIDS scientists had just learned a valuable lesson. They would have to test all their potential treatments on viruses that infected real patients.

BACK TO BASICS

The experience with soluble CD4 showed Ho that there were significant gaps in science's understanding of the life cycle of HIV. He decided to revisit his earlier Boston work on the first stages of infection. By hanging out in hospital emergency rooms and talking to colleagues, he and his team at UCLA identified four young homosexual men suffering from the flu-like symptoms of a primary HIV infection. Ho used a newly available tool of genetic engineering--the PCR test used most famously in the O.J. Simpson trial--to measure the amount of virus in the blood. Once again, he was astonished.

By this time, most researchers agreed that people in the later stages of AIDS had large quantities of HIV in their blood. But the PCR test showed that millions of viral particles were coursing through Ho's patients' blood in the earliest weeks of infection as well--as many as could be found in someone with a full-fledged case of AIDS. Within a few weeks, the viral load plunged to low and in some cases undetectable levels. The patients recovered and seemed healthy.

Ho wasn't the only scientist who had observed this. Another team, headed by George Shaw, had seen the same spike in HIV particles followed by a precipitous drop. The two researchers learned of each other's work and decided to co-publish their findings in a 1991 issue of the New England Journal of Medicine. It was the beginning of a friendly but no less keen competition between the scientists.

It was also the beginning of a new phase in Ho's career. Philanthropist Irene Diamond had decided to found an AIDS research center in New York City and had chosen Ho as its director. He was 37 years old. "I took a bit of flak because everybody said, 'He's so young, he's unknown.'" she recalls. "I said, 'I don't want a star, I want a wonderful scientist.'" For his part, Ho considered the benefits of having more lab space and secure financial backing. "It was still a risky venture," he remembers. "Marty Hirsch said, 'You're crazy. This is New York City. The politics will eat you up.'" But for Ho, the chance to do what he wanted, and to attract top-level scientists to join him, was too good to pass up.

Ho and Shaw had proved that there are high levels of virus in the first few weeks of infection. Ho and Schooley had already shown that there is a lot more virus in the end stages of AIDS than anyone had thought possible. The next question was obvious: What is going on during those middle years, when patients are still in relatively good health? Ho suspected that the answer could dramatically change the way doctors treated their HIV-positive patients.

All the blood tests indicated that the viral load was close to zero throughout the middle years, though it would gradually increase as time went by. Both Ho and Shaw realized, however, that zero doesn't always equal zero in the world of HIV. For one thing, the virus might be hiding out in the lymph nodes, where it could be producing thousands or even millions of copies of itself every day. As long as the immune system cleared those infectious particles as quickly as they formed, blood tests would show no change in viral load. "It's like a person running on a treadmill," Ho explains. It doesn't matter how fast they run. To an observer, they appear to be staying in place.

Not even the greatest marathoner could keep up that pace forever. If the virus reproduced very quickly, it would eventually exhaust the body's defenses. At least that's what Ho and Shaw thought. The trick to proving their idea was to find some way to suddenly stop the treadmill. If you did that to a jogger, he would lurch forward. Similarly, if you stopped HIV's cycle of reproduction in the blood, the immune system should suddenly rebound. By measuring that rebound, the scientists hoped to figure out just how rapidly the virus had been reproducing.

Great idea, in theory. There was just one problem: no one knew how to stop HIV that quickly. AZT wasn't powerful enough to do it. The pharmaceutical companies, however, had just started looking at a new class of substances, called protease inhibitors, that might fit the bill. As it turned out, it took several years of testing to come up with a formula for a protease inhibitor that was effective against HIV.

REINFORCEMENTS

The year was 1994, and the new drugs were finally producing good results in the test tube. They worked against laboratory strains of the virus; they worked against viral samples taken from patients. Where AZT merely slowed viral reproduction, the protease inhibitors shut it down almost completely. Unfortunately, almost wasn't good enough. It often took less than a month for a few viral particles to mutate into a strain that was resistant to protease inhibitors. The new drugs were starting to look like another failure.

But a few weeks was all that Ho and Shaw needed to conduct their rebound experiments. The two laboratories raced to find the answer.

Ho chose 20 volunteers whose T cells had dropped from a normal level of about 1,000 cells per ml of blood to fewer than 500. The newest PCR tests showed that the viral load of these patients was holding steady at about 100,000 copies per ml of blood. Ho started treating his subjects with one of the new protease inhibitors being developed by Abbott Laboratories. As expected, the amount of virus that could be measured in the patients' blood practically disappeared. The treadmill had been stopped. But no one was ready for what happened next.

Preliminary calculations indicated that the immune system was rebounding faster than anyone had thought possible. The results showed that in every day of every year, in every infected person, HIV produced not thousands, not millions, but billions of copies of itself. And every day the body launched billions of immune cells to counter the threat. The wonder was not that the immune system eventually crashed. Given such intense fighting and heavy casualties, the wonder was that it lasted so long. Ho and Shaw came up with the answer at the same time and published their results in back-to-back articles in a 1995 issue of Nature.

Suddenly the entire picture of AIDS had changed. As long as doctors thought that the virus was not very active through the early and middle years of infection, it made sense to conserve forces and delay treatment so they would be ready for the virus when it emerged from hibernation. Now it was becoming clear that the immune system needed all the help it could get right from the start.

But where would that help come from? Boston's Martin Hirsch and other virologists had already started looking to cancer research for inspiration. Oncologists have learned that it is often better to combine the firepower of several different chemotherapeutic drugs than to rely on any single medication to destroy cancer cells. Too often, they have found, the one-drug approach allows a few malignant cells to survive and blossom into an even more lethal tumor. The AIDS researchers faced a similar problem with HIV. Whenever they prescribed a single drug, such as AZT, for their patients, a few viral particles would survive and give rise to drug-resistant HIV.

Now that the protease inhibitors had become available, doctors were eager to combine them with the old standby AZT and a third drug called 3TC. A couple of mathematical models--created by one of Ho's collaborators, Alan Perelson of the Los Alamos National Laboratory--suggested that HIV would have a hard time simultaneously undergoing the minimum three mutations necessary to resist combination therapy. He placed the odds at 10 million to 1. It was at least worth a try.

HOPE AT LAST

For once in the history of HIV, a strategy that ought to work seemed in fact to succeed. Within weeks of starting combination therapy, 7 out of 10 men and women with AIDS begin to get better. Blood tests show that in many of them, the viral load has dropped below detectable levels. Relieved of the burden of fighting HIV, their long-suffering immune systems can finally tackle the deadly fungal and bacterial infections that have taken hold in their lungs, intestines and brains. Fevers break; lesions disappear; energy returns.

With the virus under control in at least some AIDS patients, doctors are considering how to rebuild their battered immune systems. After a decade of fighting HIV, many of the body's defensive reserves have been thoroughly depleted and cannot be regenerated from within. Researchers plan to grow replacement cells in the laboratory for transplant into recovering patients. Before the advent of combination therapy, no one would have considered such a rescue effort because the unchecked virus would have rapidly destroyed the new implants.

It all sounds so hopeful. Why don't scientists say at the very least that they're close to the cure? For the same reason that Ho did not promise the crowd in Vancouver that he could eliminate HIV from people in the later stages of the infection. Researchers know that after years of infection, there isn't a hiding place in the body that the virus hasn't penetrated. A cure must do much more than clear HIV from the bloodstream. It must remove the virus from the lymph nodes, the brain, the spinal fluid, the male's testes and everywhere else it may be hiding. Today's combination therapies work in the blood, but they don't reach into the brain or the testes very well.

Chances are that people in the later stages of the disease will have to stay on combination therapy the rest of their lives--assuming they can tolerate the often excruciating side effects, which range from diarrhea and fatigue to spasms, kidney stones and liver damage. They also have to bear in mind that they are probably still infectious and that eventually--perhaps in a few years, perhaps longer--their immune systems will probably once again collapse.

But what if you could avoid all those problems, Ho wondered. What if you didn't wait until the end stages of the disease but started combination therapy during the first few weeks of the infection, before too many billion viral particles had formed, before resistance became inevitable, before too many billion immune cells had died in the body's defense? Would you have tilted the odds enough in the immune system so that it could wipe out whatever stragglers might be left, wherever they were hiding?

To find out, Ho and one of his team, Dr. Martin Markowitz, recruited two dozen men in the earliest stages of infection and placed them on combination therapy. All the men appeared healthy before treatment. For them, ironically, the first signs of illness have been the side effects of the drugs they are taking, not the virus. Three have dropped out because they couldn't take the nausea and cramping.

Some of the men have been treated for more than a year. None of them show any trace of HIV in any of their blood. Ho has not forgotten, however, that zero does not always equal zero. He and Markowitz are looking for pockets of virus in the lymph tissue, the semen and the spinal fluid.

Ho believes that prospects for success are good. Assuming that nothing has been overlooked, combination therapy should burn the virus out of the body in two to three years, according to Perelson's latest mathematical models. Because treatment began so early, the men's immune systems should be able to replace any lost defensive cells. There is still a chance that bits of the virus, called proviral dna, are lodged in the chromosomes, beyond the reach of even the most powerful drugs. Ho has studied these vestigial snippets of genetic information and believes they are defective and cannot give rise to a new generation of HIV. Other scientists are not so sure. The only way to find out is to stop the medication and see if the virus comes back.

None of Ho's patients plan to take that step anytime soon. And he doesn't blame them. Just a few surviving viruses could manufacture enough copies to resaturate a body in a matter of days, forcing the patient to start the long treatment process all over again. But at least one of Ho's patients has agreed to stop taking his drugs in another year or two--after his doctors assure him that tests show no evidence of HIV in his lymph, semen, spinal fluid or elsewhere in his body. When he does, we will know, probably within a few weeks, whether the virus has returned or whether it is gone for good.

Even if the virus stages a comeback, that doesn't necessarily mean that combination therapy has totally failed. It may be that additional ingredients could eliminate the virus completely. Ho has already started using a combination of four drugs in another early-intervention trial. And he has access to new, experimental medications that can better penetrate the brain and perhaps the testes. These drugs may help patients in later stages of the disease whose infections have become resistant to current treatments.

There is still a long way to go, both in the quest for an effective treatment and in the search for a way to prevent infection in the first place. In the flush of the new optimism, some scientists are more hopeful about the prospects for gene therapy, which could possibly make the immune system impervious to HIV attack. Another promising line of research centers on a group of molecules called chemokines, which may one day be used to shield cells from HIV. Other scientists, including Ho, are intensifying their search for a vaccine. Two weeks ago, the nih increased its budget for AIDS-vaccine research 18%--to $129 million--and named Nobel-prizewinning molecular biologist David Baltimore to head the effort.

It has taken the collaborative work of thousands of scientists and physicians to get this far. It will take even greater cooperation and well-funded coordination to overcome the remaining hurdles. But the worst fear--the one that seeded a decade with despair, the foreboding sense that the AIDS virus might be invincible--has finally been subdued.

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