VIRUSMYTH HOMEPAGE

SEARCHING FOR DR. HO

By Colman Jones

Now On 1997

Colman Jones goes to Washington to track down the most famous (and controversial) AIDS star

WASHINGTON, DC -- There's tension in the posh lobby of the U.S. capital's Sheraton Hotel, where security guards are nervously adjusting their wireless earphones.

A strange situation, considering that this is supposed to be a mild-mannered medical affair. The Fourth Conference On Retroviruses And Opportunistic Infections is the only major scientific forum on AIDS in North America this year. With all the recent hoopla surrounding the prospect of "eradicating" AIDS with new combinations of high-tech drugs, thousands have descended upon this hotel to get all the latest updates. Among them are a few people with AIDS who aren't on the guest list but who are determined to get in all the same.

At the centre of the storm stands David Ho, Time magazine's Man of the Year for 1996, the virologist who has become the disease's latest cause celebre. Ho, director of the prestigious Aaron Diamond Research Centre in New York, is credited not only with figuring out how HIV works inside the body but also with discovering a series of drugs that appear to make it go away -- at least for now.

In the midst of all the media accolades, some scientists are voicing caution about the reports coming out of Ho's lab. Although the new protease inhibitor drugs appear to be helping many people with AIDS (see NOW, January 9-15), no one is sure exactly when to start using them, which ones to use or how long their benefits will last.

Other critics argue that Ho's theory of HIV dynamics -- the virus locked in a pitched battle with the immune system from day one -- is nothing but a hypothetical construct that in turn is based on complex mathematical modelling that may not hold up in the real world.

Bob Gallo, the original AIDS pioneer credited with co-discovering HIV in 1984, has little use for Ho's novel ideas about how the virus behaves inside the body.

"I've never read his model, and I never would," says Gallo, the U.S. government's senior AIDS researcher in the 1980s. "There's no new paradigm to me. I just think it's a lot of noise."

Gallo's skepticism about Ho's theories is shared by other scientists, like Jay Levy, another veteran HIV researcher at the University of California in San Francisco. But these dissenting voices are largely absent from this meeting, which is organized by an elite club of scientists who govern AIDS research in North America.

Indeed, hundreds of doctors and researchers have been turned away from the event that some charge is "in the hands of a few self-selected individuals whose views and preferences dominate every aspect of the program," to quote Martin Delaney, founder of San Francisco's Project Inform, one of the oldest AIDS service organizations around.

Scientific favouritism

Delaney's group is part of a coalition of U.S. AIDS groups using the opening day here to launch a public campaign designed to persuade the organizers to radically rethink the design of their gathering. Now that the international conferences are only held biannually, activists want this meeting expanded in order to make more room for people with AIDS and broaden its scientific focus.

Conference organizers reject accusations of scientific favouritism, but there's no denying this meeting's overarching emphasis on fighting AIDS through expensive cocktails of high-tech drugs, a strategy that holds little relevance for the vast majority of the world's infected populations.

I'm here to find out how AIDS research has arrived at this latest juncture in its development, and to unlock the secrets behind the man who's now the centre of attention -- David Ho.

* * *

I enter the gigantic hotel ballroom for the opening evening session, which features a keynote lecture by Ho, who's introduced by conference chair Douglas Richman. Taking a cue from the Time magazine spread, Richman shows us grainy snapshots of the Ho family as he recounts the young Taiwan-born researcher's climb to the upper echelons of AIDS research. Ho then takes the podium, his round and boyish features amplified by a massive array of speakers and TV screens.

The short, mild-mannered father of three appears ill at ease with his newfound status as AIDS celebrity, expressing his hesitance at being singled out as Man of the Year, insisting the coveted honour be shared among his colleagues. He then recites the now-familiar data that has tantalized the world for months in a talk entitled Can HIV Be Eradicated From An Infected Person?

The answer to that question, Ho admits, isn't known, and won't be known until doctors feel confident enough to take people off the new drugs, at which point the virus could still return with a vengeance, as has already been seen in some cases. He's quick to caution that this apparent eradication of HIV, achieved in the first few months of infection, may not necessarily be possible in people who've been infected for years.

My attempts to set up an appointment with Ho before heading down to Washington were unsuccessful, Sidney Ho -- David's brother and the centre's operations manager -- insisting that no interviews were being granted. But when I spot the diminutive scientist in a hallway here at the conference, I can't help but amble over to see if I can quiz him for a few minutes. He can't talk now, he says, but instructs me to call his hotel room later, though he's visibly unenthusiastic about yet another round of Q & A.

But there's a specific reason I want to talk to Ho. It centres on a key piece of research he published back in early 1995, one that has guided the consensus view of HIV infection and its treatment.

Ho's team, along with one in Alabama, claimed to show much more HIV activity in people with AIDS than was previously thought, with the virus attacking the critical CD4 cells of the immune system from the first moment of infection. According to Ho, HIV and the cells of the immune system are constantly regenerating at high rates, with 1 billion new CD4 cells being produced every day to fight off the equally prolific virus.

HIV finally wins the battle, the theory goes, and kills more cells than the body can produce, leading to immune collapse. Ho uses a colourful analogy, comparing the loss of CD4 cells in advanced HIV infection to "a sink containing a low water level, with the tap and the drain both equally wide open."

But major questions have been raised about this new construct of HIV pathogenesis, both in the scientific literature and at other conferences. For example, a series of letters by other HIV researchers appeared in Nature following the publication of his 1995 paper, questioning the mathematical models used in calculating the numbers of cells and viruses.

Claims challenged

More recently, a study published in Science magazine last November by a team of researchers in Holland appears to contradict one of Ho's chief claims, namely, that the critical CD4 cells of the immune system undergo a rapid rate of renewal during early HIV infection.

Every time a cell divides, it loses a fragment from the extreme ends of its chromosome, known as telomeres. The Dutch researchers analyzed cells taken from HIV-positive men over a period of several years. They found no evidence that the telomere lengths of the cells were shortening over time, implying that cells were not in fact replicating at anywhere near the rates claimed by Ho and his colleagues.

Frank Miedema, a leading immunologist at the Netherlands Red Cross Blood Transfusion service, insists that "There is no more cell turnover than we have in a normal individual.

Doctor's dogma

"There is no exhaustion of the immune system at all," says Miedema, in an interview from Amsterdam. "At this point in time, David's sink model is out. All the data argues against it."

But Miedema is reluctant to confront the big guns in the U.S. "I was not at the Washington meeting, but if the guys had had the guts to invite me, I would have presented the data.

"If people find it interesting to have this debate, they would invite people to do that, and it didn't happen." Why not? "The dogma that is now out there in HIV infection is David Ho's dogma," Miedema suggests.

He notes that these questions about how the immune system breaks down in AIDS bear great relevance to future treatment. "This is the most critical question in AIDS pathogenesis. If you want to understand the underlying mechanism by which people die from AIDS, this is not academic -- this might be very critical."

Miedema is quick to add that he considers Ho's work otherwise outstanding. "He has a done of lot of things, he has organized a good laboratory," he concedes, "but sometimes these people can be wrong."

I'm eager to press Ho for a response to these scientific challenges. But when I call at the appointed time, Ho isn't in his room, I'm told by his brother Sidney, who answers the phone. Interviewing the Man of the Year isn't going to be easy, I'm discovering.

Ho wasn't always top gun in AIDS research, of course. Bob Gallo once dominated AIDS conferences like this one, but the retrovirologist has since been relegated to the sidelines by Ho and the new generation of AIDS whiz kids.

I walk up to Gallo after his session and introduce myself, reminding him of a telephone conversation we had some years ago. He invites me to the hotel bar for a drink with his friends.

As we sit down, I ask Gallo what he thinks of Ho's much-talked-about "open-sink" model. The elder AIDS scientist shrugs his shoulders. "The tenet that you treat against a microbe as early as possible was there ever since we knew HIV caused the disease," Gallo says. "You don't need fancy models. David is a good investigator, he seems competent as far as I know. The rest of it is hoopla -- that's all I can say."

Treat early

Hoopla perhaps, but Ho's findings are nonetheless being taken as a cue by many doctors here to treat people with HIV as early as possible with a combination of powerful drugs, using measurements of virus activity -- known as viral load tests -- to gauge how well the treatment is working.

In San Francisco, Jay Levy, who's cared for people with AIDS since the beginning of the epidemic, cautions that levels of HIV in the blood are only one factor in making treatment decisions. "I have tremendous reservations about using numbers to decide on therapy. We will consider the viral load, but we look more at the immune response and we certainly consider the basic clinical condition of the patient. If the immune system is doing its job, just having the virus floating around -- most of it noninfectious -- is not a major factor."

As with AZT years ago, concerns are being raised about rushing people onto combinations of drugs whose long-term effects remain unknown. "(Ho and Richman) believe that you should start treating right away -- I don't," Levy states bluntly. "Once you use therapy, you've committed that person to therapy for a lifetime."

While Ho's initial results have generated a lot of hope within the AIDS community, everyone is waiting to see what the future holds. "It's very exciting, but he hasn't proved anything yet," notes Jose Sousa, an AIDS activist with the Community Treatment Advocacy Council in Montreal, who's among those refused admission by conference organizers and left to wander the halls and piece together information from the sessions unfolding inside.

To Sousa, Ho's findings are no cause for celebration. "Right now, he's putting out a lot of false hope, which is not there for those of us who have been infected for years. So why is he Man of the Year?"

Most impact

According to Nancy Kearney, public affairs manager for Time magazine in New York, it's because Ho is "the person who has made the most impact on the news. As the article clearly points out, his treatment is not a cure," Kearney is quick to add, "but it was a breakthrough year in AIDS research, primarily because of his work."

Meanwhile, the conference is abuzz with new statistics released by the New York City health department indicating that deaths from AIDS in that city have plummeted sharply in the last year, a drop credited to the introduction of the new treatments. Clearly, something is happening, but AIDS advocates -- like John James, editor of the widely read newsletter AIDS Treatment News -- warn that it's too soon to break out the champagne.

"There has been a major advance in the last year," James notes, "but it doesn't work for everybody. And even when it does work, we don't know for how long. There is intolerance to the drugs, there's drug resistance, there are compliance problems, interaction problems -- there are all sorts of problems, and we don't know what the outcome is going to be."

Another concern centres on whether the simple increases in CD4 cell counts that have been documented with the new medications represent a true reconstitution of the immune system. Mervyn Silverman, former president of the American Foundation for AIDS Research (AMFAR), notes that "Even though you get a buildup in CD4 cells, they may not be the old ones you lost -- they may just be more of the same that you have. And that may mean you may not be able to fight off certain opportunistic infections."

According to several scientists I spoke to -- including some who weren't invited to this meeting -- there's too much emphasis here on the virological aspects of the disease and not enough attention paid to the immune system and how it regulates itself.

"The best way you control an infectious agent," Levy insists from his office in San Francisco, "is through the immune system."

Clinical immunologist Jeffrey Laurence, director of Cornell University's AIDS lab and a senior scientist at AMFAR, agrees that research into the immune aspects of AIDS is long overdue. "These conferences, because they've mainly been based on infectious disease experts, have historically concentrated on finding a new drug," Laurence points out, "and the immune therapy side has been ignored."

I go looking for a response from Richman, the conference chair, whom I eventually find in the poster area chatting with colleagues. He has to rush off to a meeting shortly, he tells me, but agrees to chat briefly as we walk down the hall, his bodyguard following close behind.

Richman insists that space constraints prevented admitting more people to the meeting. "It's limited capacity, and we tried to set up as fair and balanced rules as we could to let people in according to the time of submission and other things. This is a standard thing -- there are lots of meetings with limited scientific capacity."

Organizer upset

Richman grows upset when I confront him with the activist groups' press release, which he labels "trash" and "demagogy." He vigorously denies charges of scientific elitism, insisting that "If Jay Levy isn't here, it's for other reasons." He then abruptly cuts me off and walks away toward another group of scientists, anxious to get away from the prodding.

Reached later by phone in San Francisco, Levy is quick to point out that "This is the fourth year they've decided not to have my views on the program, because Ho and Richman run the conference. It's gotten to be a political event again.

"It's like a narrow little corner here," Delaney says. "Everything is protease inhibitors and viremia (virus production), and I just think that's a trap. It's a trap we've fallen into before, and it's dumb of us to fall into it again, however attractive the bait may look."

Back in the spacious ballroom, I move toward the front to discover Ho surrounded by a flock of journalists, microphones in hand. While patiently awaiting my turn, I'm accosted by a security guard, however, who forcibly insists that I accompany him out of the area. "The doctor is too busy for any more interviews," I'm told.

I attempt to stand my ground, citing his earlier willingness to talk, but within seconds Ho is whisked out a side entrance by his entourage. I know which direction they're headed and try to outrun them. After a mad dash across the hotel complex, I finally manage to intercept the doctor, his brother and another colleague as they head down a hall toward the elevator.

It's clear in an instant that Ho hasn't the slightest intention of talking to me, and my requests for an interview fall on deaf ears. Sidney hustles his star brother away, turning only to bid me goodbye as the trio disappears down the hall.

Ho's unwillingness to be challenged is both frustrating and unsettling, in the face of all the unknowns surrounding his research. Whether he and his colleagues will continue to dominate the field will largely depend on how well these new drugs pan out in the long run. But a groundswell of opinion is slowly emerging that views the contribution of Ho and his colleagues as only one -- perhaps small -- part of a much larger AIDS puzzle. *

VIRUSMYTH HOMEPAGE