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If you like David Ho's story, you might also like:
Paul Farmer,
John Gearhart,
Jeong Kim,
Antonia Novello,
Jonas Salk and
Bert Vogelstein

David Ho also appears in the video:
Frontiers of Medicine

Related Links:
Aaron Diamond AIDS Research Center
PBS

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David Ho
 
David Ho
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David Ho Interview (page: 4 / 6)

AIDS Research Pioneer

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  David Ho

I understand you attempted a very important experiment with CD4 molecules that didn't work out. Could you tell us about that?

David Ho: The CD4 molecule is necessary for HIV to bind to before it can enter the cell. We thought if we could make free soluble forms of this CD4, they would serve as decoys for the virus and help block the entry of the virus into the cell. It's a very logical thing to think of, and using molecular techniques several groups actually came up with such a strategy. We helped test it, and showed that it wasn't working. When we figured out why, we learned a very important lesson.

Up to that point in 1989, people had been studying HIV grown in the laboratory and had not concentrated on HIV as it exists in the body of infected individuals. It turns out they're not the same. HIV grown in the laboratory is very susceptible to this approach and the drugs were developed based on use of these laboratory viruses, and when soluble CD4 was applied to viruses that came directly from patients, it simply didn't work. There's a cloud of sugar around the virus cells to protect against antibodies, so the virus has a protective mechanism. It's one of the reasons we're having such trouble in coming up with a vaccine.

When an experiment doesn't work, you may learn a great deal anyway, but it must be crushing when you've spent a lot of time on it.

David Ho: It's crushing in some ways but it led to a new set of findings, and that's pretty exciting.


We went into the experiment expecting to see some positive effect of the approach, and it didn't come up and we thought, "Well, maybe it's only this case. Let's wait until one and many more," and repeatedly it failed and failed. We were more interested in finding out why because there has to be an answer there. And, that process was pretty exciting, to be the one showing that it doesn't work although we wanted the positive result rather than the negative result, but that's science. You get a negative result and now you have to figure out why because it works beautifully in the test tube. Why isn't it working in the patient? And that answer and that discovery process really taught us a lot about HIV. And, this is the joy of science because you go into it because you're curious and you figure things out and you say, "Wow."

[ Key to Success ] Perseverance


Did you ever feel disheartened or want to quit and do something easier than this?


David Ho: I felt disheartened and beaten for a long time. Even though the science was coming out positively, we weren't making much progress for the patients. So, as scientists we could sit and celebrate each successful experiment, but we made very little difference to the lives of patients with HIV infection and that was very disheartening. And, seeing lots of patients go over that decade and almost a decade and a half is quite devastating, but I never said, "This is too disheartening. I'm going to quit." We were learning so much about the virus, one optimistically could expect some progress to come along. And, in fact, it did come along in 1994 when the protease inhibitors first went into human testing.

[ Key to Success ] Perseverance


We had worked on such inhibitors in the laboratory in the late '80s and early '90s. No one paid any attention, and it was only through the clinical application and the results that the recognition came. We now had a powerful tool to fight HIV, and people were finding out that combining the older drugs was also powerful. We were strategically placed in 1994 to combine the protease inhibitors with several of the old drugs. We could knock the virus down so it's no longer measurable, and if the patient could tolerate the drugs we could keep it down for two to three years. That's where we are today. Even though it's not gone, we can control it. Not in everyone, but in many, many patients, and this result is reflected in the national statistics.

How have the statistics changed?

David Ho: If one looks at the inpatient census for AIDS patients, it's gone way down. These complicated infections that we call opportunistic infections have gone way down. Most importantly, AIDS mortality has gone down about 50 percent in each of the last two years. Lots of patients have turned around from a very sick state to a functional state where they are able to return to their jobs.

When did you realize you were onto something that could really help people?

David Ho: The first 20 patients we gave the protease inhibitors to showed us how potent these drugs were in the body, not just in the test tube. The virus fell ten fold, then a hundred fold, and in some cases a thousand fold in a matter of a few weeks. The patients put on weight, became functional. The sick ones resolved their problems. It was very dramatic.


We also knew that if you gave the drugs one at a time, the virus replicates so fast that you will create the mutations necessary to become resistant to the drugs. And, therefore, if the drugs were given individually, the virus would find a way to evade the drugs. And so, during that period, we did a lot of mathematics to calculate what it would take to control the virus with great potency and with great durability. And, for a period in 1994, it was truly an exciting phase in my professional career. One would go to bed thinking about it, waking up in the middle of the night thinking about what we're looking at, what this piece of evidence means and how do we take this and translate it into practical application.

[ Key to Success ] Passion



A lot of what we're looking at is the result of that process from our lab as well as the laboratories of several groups around the world, basically realizing the kinetics of the virus, using that information to do calculations. And, this is where my physical science background really came in useful, having a strong background in mathematics and applying it to biology and then being able to go on with a hypothesis, saying that if we approach treatment in this fashion with these types of drugs in combination, these are the results we expect. And, most of that has come true over the last few years, and now we need to see how far we could go with this whole strategy.

[ Key to Success ] Preparation


How do the protease inhibitors work?

David Ho: The protease is an enzyme for the virus. This enzyme is a chemical scissor. HIV makes its proteins in big chunks, and this enzyme cuts them into six or seven small pieces. If the enzyme does not make the cuts, the proteins are inappropriate. They won't form the full mature progeny particle.


The protease structure had been studied for a long time. Particularly in the late '80s we realized what it looked like three dimensionally, and there's a cavity in the middle. And inside that cavity are the enzymatic sites, or the cutting sites. And so, the big proteins could come and sit in this groove and then be cut. Well it was easy to think that if you could fill that cavity with a small chemical so the proteins could not be cut. And so many, many groups started to try to fill that cavity with small chemicals, and there were rationally designed chemicals -- as well as chemicals that were done by a more empirical screening process -- that would fill this cavity. And so, what protease inhibitors are is simply something that would gum up the chemicals. So now HIV could not cut its proteins, and so it makes that progeny, and therefore it can't spread the infection. As long as the patient is taking the drug, it can't spread the infection. So it's now kept in control.

[ Key to Success ] Vision


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This page last revised on Feb 29, 2008 12:37 EDT