Dr. David Ho was sitting in the audience during an AIDS meeting in 2007 when the presenter flashed a cartoon onscreen to make a point. Along with his colleagues, Ho chuckled at the image of a blindfolded baseball player swinging mightily at an incoming pitch. But as amused as the scientists were, they were sobered too; they knew that the player in the cartoon was them. A swing and a miss, the image was saying, one of many in the long battle against AIDS.
Ho certainly got the message. For nearly a quarter of a century, he and other AIDS scientists had been whiffing repeatedly, failing to make contact as HIV stymied them again and again. Powerful drugs to foil HIV could do only so much. To corral the epidemic and truly prevent HIV, only a vaccine would do. The problem was that no vaccine strategy had ever succeeded in blocking the virus from infecting new hosts, and that wasn't likely to change in the near future. "It struck a special chord with me," says Ho of the baseball image. "I think it accurately pictured our chance of success. We all felt that frustration." (See the top 10 medical breakthroughs of 2009.)
The excitement over those advances, however, has been tempered by the still raw memories of a humbling retreat in 2007, after a highly anticipated shot against the virus was deemed a failure. While nobody expected spectacular results, neither did anyone expect such a stunning defeat, and the scientific community is still struggling to recover from it. "We are still a long ways away from having an effective HIV vaccine that physicians can reach into the cabinet and pull out in a vial and inject into a person," says Dr. Bruce Walker, an HIV expert at Harvard Medical School. (See the top 10 scientific discoveries of 2009.)
That may be true, but Ho, who has been working to develop an HIV vaccine of his own, now believes that a traditional shot, one that relies on snippets of a virus to both awaken and prod the immune system to churn out antibodies, may not be the best way to fight HIV. Rather than expecting the body to do all the work of first recognizing then mounting an attack against the virus, why not just present the body with a ready-made arsenal of antibodies that can home in on HIV? It's the immunological equivalent of a frozen dinner; the already cooked antibodies eliminate all the hard work of prepping and priming the immune system to do battle.
It's a bold strategy and one that has never been tried before in the AIDS field, but Ho is willing to stake his reputation and that of his nearly 20-year-old facility, the Aaron Diamond AIDS Research Center (ADARC) in New York City, on his hunch. So is the Bill & Melinda Gates Foundation, which has steered nearly $7 million his way to pursue the theory. Ho has redirected more than half of his lab to the project, and the results so far have reignited his passion for discovery; he's now back at the lab bench overseeing experiments.
Ho can't help breaking into a grin whenever he discusses the new project, and smiles haven't come easily to him of late. In the 1990s, he and ADARC established themselves as leaders in the AIDS field by pioneering the early use of the antiretroviral (ARV) cocktails that have reduced the death rate from AIDS (for which Ho was named TIME's Person of the Year in 1996). But in recent years, the center has suffered a series of setbacks, including a scientific paper that required a partial retraction, and the departure of key scientists. These challenges have some in the field wondering whether ADARC — and its golden-boy director — are on the verge of the next big breakthrough in AIDS or are wandering down yet another detour in the long and maddening fight against the disease.
First Responder
Whatever successes Ho does or doesn't have ahead of him, he long ago earned his credentials in the AIDS field. As a physician at the University of California, Los Angeles, in the early 1980s, he began keeping a diary of patients who were rushed to the emergency room with a mysterious amalgam of symptoms such as pneumonia, cancer and, most important, a devastating drop in immune function. After a few months, he noticed a pattern: most of the patients were gay men. Intrigued, he became nearly obsessive about chronicling the growing wave of cases. Within two years, Ho and the rest of the world would know that they were seeing the first cases of AIDS.
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Ho's preoccupation with HIV only grew as the virus continued to baffle scientists. Expecting the unexpected was the best way to confront HIV, he soon learned, and he quickly amassed an impressive array of scientific firsts in the field. As director of ADARC, which was founded in 1991 and was one of the first research centers dedicated solely to the study of AIDS, he led a team that pioneered the "hit 'em early and hit 'em hard" approach to drug therapy, now the core of the ARV-cocktail treatment that is keeping millions of HIV-positive patients alive. His lab showed how HIV therapies would be most effective in the days and weeks immediately after HIV infected a new host. That understanding came from their breakthrough finding that rather than sitting latent for years after infection, as many experts believed at the time, HIV was actively challenging the immune system from Day One. Soon after that revelation, ADARC scientists were the first to add to existing data on how HIV worked by identifying a second, key receptor that the virus uses to invade cells.
Vaccines in Vain
But while AIDS scientists began making inroads in developing drug therapies, designing a vaccine was proving nearly impossible. Despite all that they have learned about HIV, experts are still missing one essential ingredient: to this day, they do not know exactly what cells or immune responses could protect the body from HIV infection. Could an antibody that binds to and neutralizes the virus do the trick? Are T cells, specially formulated to recognize portions of HIV's surface proteins, the solution? Or, as many experts now suspect, is some elusive combination of those factors the key to outwitting HIV? (See TIME's photo-essay "Access to Life.")
Without an answer, developing vaccines is a very halting process. "The virus is a moving target," says Dr. Gary Nabel, director of the Vaccine Research Center at the National Institutes of Health (NIH). "It is constantly changing its genetic makeup through mutations. It's also a moving target because the proteins of the virus surface are actually moving themselves — they are conformationally flexible. The net result is that the immune system never gets a really good look at them."
It didn't take long before these futile efforts began to wear on the researchers in the field, not least of all those at ADARC, where Ho's group was attempting to develop its own vaccine — with little success. The center — which had earned such laurels for its ARV triumph — began to suffer a scientific slump and lack of direction, according to those who left in the early 2000s. Some blame Ho's management style, which, they say, changed in the aftermath of media attention that came with his recognition as Person of the Year. They describe a highly competitive atmosphere in which members scrambled to claim key projects and kept certain studies under wraps out of fear that colleagues would poach their ideas. Frustrated, several high-level faculty members, none of whom agreed to be quoted by name, decamped. (Watch TIME's video "New Hope for Kids with AIDS.")
"ADARC was a great experience," says one, who now heads an immunology lab at a major university. "Those were really great times, and you don't experience them often in an academic career. The structure put in place for the first few years was magnificent and very collegial. But unfortunately the happy ending didn't go forth."
The malaise at the lab, which Ho attributes to personality conflicts among the faculty, began to infect the quality of the science. In 2002, Ho generated headlines when he thought he had found the X factor made by immune cells that protected some people from developing AIDS. It turned out, however, that his conclusion was premature. Other cells had contaminated his results, and he was forced to issue a "retraction of an interpretation" of the paper describing the study. "It was an embarrassing moment for us, but we fixed it ourselves," says Ho. "It was certainly a low point in our history here."
ADARC had plenty of company. Vaccine efforts were progressing elsewhere in the AIDS community, but unevenly. Testing for one candidate, made by Merck, began in 2004 with much fanfare and ended three years later with disappointing results: not only had the vaccine not offered protection against HIV infection, but it actually seemed to increase the risk for some people. Because of the Merck results, the NIH, which had a similar vaccine in the works, put off plans for its own study.
"The year to two years after the disclosure of those results had to be among the most bleak of times for AIDS-vaccine scientists," says Nabel. "We questioned just about everything we were doing."
The Clouds Part
But by early 2007, Ho had already glimpsed the possibility of an answer. In Houston the biotech firm Tanox had developed a compound that it thought might interest him. Ho knew Tanox well. He is a friend of one of the company's co-founders and is a member of its scientific-advisory board, so if the scientists there thought they were onto something, he suspected it was worth a look.
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He flew to Houston, where he was given a briefing on a new agent called ibalizumab, an antibody that appeared able to block HIV's entry into healthy cells. In the 200 or so HIV-positive patients tested in the early trial, the compound was effective, but Tanox was worried about resistance. No matter how promising ARV drugs were, HIV inevitably found a way to evade them. So while the agent seemed to reduce the burden of virus in the blood up to 90% in patients with full-blown AIDS, no one knew how long the viral standoff would last. The company's leaders wanted Ho's opinion on whether the agent was worth developing further.
Looking at the numbers, Ho saw more than just another member of the growing arsenal of ARV cocktails. Each of the ARVs focuses on thwarting just one of several different steps in HIV's infection process. Ibalizumab works at the critical juncture where the virus meets a healthy CD4 cell — a critical component of the immune system — essentially interposing itself between the two and preventing infection. If ibalizumab was so good at tamping down HIV in AIDS patients who were already infected, then maybe it could be tweaked to prevent AIDS in the first place. In other words, maybe it could become a vaccine — just a whole different kind of vaccine that bypassed the traditional, and frustrating, process of figuring out what the immune system needs to fight HIV. (See pictures of the Red Cross.)
Ho didn't even wait to leave the meeting before phoning his lab with instructions to investigate the literature on ibalizumab. "He was so excited about it," says Yaoxing Huang, who received the call and is now one of the two researchers Ho has diverted to investigating the compound. Barely three years later, that initial enthusiasm has only grown, spreading throughout the labs that occupy two floors at ADARC's Lower East Side facility.
What the ADARC scientists are struggling to achieve is a thorough understanding of how ibalizumab operates and how they can control those machinations. The CD4 cell is a bit like an immunological sentinel, endowed with the ability to recognize snippets of various pathogens, from common influenza to HIV, and mark them for destruction by other cells. Once attached to a CD4, HIV begins an intricate series of steps to gain entry into the cell. Ibalizumab is able to disrupt this intricate molecular choreography by binding to the CD4 and serving as an immunological snare. With the antibody stuck to the CD4 receptor, the virus is physically unable to complete the necessary contortions it must perform to slide into the cell and take over its genetic machinery to pump out more virus.
That's the beautifully elegant scenario that attracted Ho to the antibody, but the problem is that tying up CD4 this way may not be such a good idea. Taking so many of the body's essential defense cells out of commission means the patient may be left vulnerable to any number of other infectious agents — exactly the immunocompromised position that AIDS patients are trying to avoid. That was the fear that Ho's lab members expressed when he broached the idea.
"My initial reaction was, Are you crazy?" recalls Sandy Vasan, a researcher at ADARC who, along with Ho and Huang, is now heading the ibalizumab studies. A clinician who sees patients, Vasan says, "It's really scary to want to put an antibody on CD4. You need CD4." (See "The Year in Health 2009: From A to Z.")
But Ho believes ibalizumab is more agile than that. CD4, it turns out, is like a marina with several docks; HIV berths in one, and ibalizumab in another, leaving the cell free to fight other pathogens. "If CD4's binding site to HIV is with its nose, then this antibody is binding to the back of CD4's neck," Ho says. That means the cell's ability to function as a pathogen troller is not impaired by being coupled to ibalizumab. "There is a solid scientific rationale for what they are attempting to do," says Harvard's Walker.
The lab is now working with monkeys to test whether ibalizumab can head off infection not just with the notoriously weaker lab strains of HIV but also but with naturally circulating strains as well. The idea is to hit the antibody with the most potent HIV around, so if the strategy doesn't work, Ho can shut down the project, before it gets too far along.
Ho is hoping it won't come to that. He is not under any illusion that a successful antibody-based treatment will have the sweeping effect of the polio or measles or smallpox vaccines — essentially wiping out the diseases in treated populations. Instead, an ibalizumab-based therapy will be just one of many weapons against HIV, albeit a very powerful one. "At our first meeting on this, I said I have a strategy that I feel will work," Ho recalls. "It was truly my gut feeling."
It takes more than instinct to make good science, of course, and Ho is keenly aware of that. But like a talented batter, he's hoping that a combination of intuition and technical skill will guide him to make contact. A solid hit would be nice — but Ho is still trying for a home run.
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