David Ho: The Man Who Could Beat AIDS

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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