Frontline World

Hong Kong - Chasing the Virus, June 2003

Related Features THE STORY
Synopsis of "Chasing the Virus"

Tracing Disease Outbreaks

On the Trail of a Killer

Scientists spell out their approach to SARS

International Health Organizations, Search for a Quick Cure, Economic Fallout




PEPTIDES, ANTIBODIES, MEMBRANES... WHAT? Scientists spell out their approach to SARS
When SARS cases broke out among human beings for the first time, early this year, it didn't take long for scientists around the world to begin collaborating on ways to stop the disease. Reporting from the epicenter of the SARS outbreak in Hong Kong, FRONTLINE/World's Renata Simone caught up with an international team of researchers during their experimental trials on a possible treatment for SARS. In this overview of the science being brought to bear on the new virus, three of the researchers -- Malik Peiris, David Ho and Richard Kao -- explain what was happening under the microscope in a series of experiments they conducted at the University of Hong Kong in May 2003.

Identifying a Virus
Dr. Malik Peiris explains how the team discovered that SARS was a type of virus known as a coronavirus. They also determined that SARS was unique, never having been detected in animals or human beings before.

Making the AIDS Connection
Dr. David Ho, known worldwide for innovative AIDS research, outlines the connection between AIDS research and SARS research. Ho and his colleague, Dr. LinQi Zhang, try treating SARS-infected cells with methods similar to those that have worked with AIDS.

Getting Results
Dr. Richard Kao talks about the breakthrough for the team, when they find that one of the substances they've used to treat cells seems to prevent the cells from becoming infected by SARS.

Malik Peiris

Malik Peiris
Malik Peiris
Assistant Dean, Department of Microbiology, University of Hong Kong
May 3, 2003

Tell us about that moment when you figured out you had a unique virus.

What we were seeing was something from these patients' clinical specimens that was killing the cells. Of course there are other things that can cause this type of effect, but viruses are among them. We went on to show that we could actually transfer this [result] to new cells and the new cells also would die in the same fashion -- so we were quite confident that it was a virus. We wanted to be more certain that the virus we had [identified] had something to do with the disease of SARS. [In the meantime, the World Health Organization had coined the term SARS to cover this emerging disease.]

Illustration of the lifecycle of a coronavirusWhat we did was take blood samples from a number of other patients who had typical SARS and test their blood to see if they had antibodies to this virus that they got. And to our great excitement we found that patient after patient who had clinical SARS had antibodies that reacted with this virus. When they looked at blood from other patients they had no antibodies to the virus. So that really was the time I think we were confident that we really had the virus causing SARS captured.

Talk about the speed of the discovery.

At that point, we knew we had the virus that causes SARS. But we did not know what this virus was. We then took a train track approach. On the one hand, we tried to look at the virus under the electron microscope to see what it looks like. It looked like coronavirus. Corona viruses are viruses that have spikes on their surface, and the term corona comes from "crown," the spikes on a crown, so to speak.

While we were taking that [track], my colleague Leo Poon, who is a molecular virologist, was going on a blind fishing expedition trying to fish out genes of something unknown from these infected cells. I think he tried 38 times or so and fished out total rubbish. But on the 39th try he fished out something. Then he sequenced that and matched that sequence with what sequences are available in the public databases of genetic sequences. It seemed to be very similar to the family of coronaviruses. At that point of course the conclusion was obvious: You're dealing with a coronavirus.

The next question was where did this virus come from? This was not one of the known human coronaviruses. There are two coronaviruses that are very common in humans. They cause the common cold, they're very trivial, and do not cause [behavior] anything like this. From the way it was behaving in the laboratory, it was not like one of the normal human coronaviruses.

How was this virus different from other coronaviruses?

It was growing in types of cell cultures that normally they wouldn't grow in. We compared the genetic fragment that we had with other coronaviruses that are known, human and animal, and you could see that this one was sticking out like a sore thumb. Our tentative conclusion at that point was that we were dealing with a new virus that was probably not present in humans before. When we looked at blood from mammal and human subjects in Hong Kong, no one had any antibody to this virus except patients who had the disease. So it [seemed clear that the virus] was not something that was kicking around in humans before. So we were confident it was not a human coronavirus. But it was also not one of the recognized animal coronaviruses. The conclusion had to be that it was coming from some type of animal, but it was a virus that was new to science.

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David Ho

David Ho
David Ho
Director, Aaron Diamond AIDS Research Center
May 3, 2003

Explain how your experience in AIDS research led to this experiment.

Well you know HIV binds to a CD4 T-cell, right?

Like any virus?

Right, any virus [does this]. HIV does so by binding to the CD4 receptor and CCR5 co-receptor. After engaging these receptors, a fusion protein called GP41 [forms on the surface of the virus].

Viruses, then, attach to the CD4 cells in two places?

Illustration of HIV cell attacking a healthy T-cellSome just attach in one, but HIV attaches to two. We don't know about SARS yet. After attachment, the GP41 is the one that mediates a fusion. It's like a harpoon, so it uncoils and just tosses the sharp part into the membrane. Then what happens is that what we call HR1 and HR2 [heptad repeats] form an alpha-helical coil. The HR1 and HR2 yank the membrane close to the virus membrane and the two fuse. [That's how] the virus gets inside the cell. T20 [a peptide synthesized to disable HIV's entry into cells] is a mimic of HR2, so that it gums this process up. It's a competitive inhibitor. It gums it up so that the virus cannot yank the membrane toward itself.

Is this something like sticking something into a hinge or door jam?

Right. When the SARS virus sequence came out, we looked at the envelope protein, the spiked protein on the surface and figured out just by analogy that there's a portion that's probably binding a receptor. If you look, there's a portion that looks like HR1 or HR2. So we simply made peptides that look like HR1 or HR2. We made twelve of them and now several of them are blocking this process, we think.

The peptides are gumming up the works?

Right, gumming up the works. Obviously, some [peptides] are more potent than others. And I don't think it's extremely original. We just [focused on] what we can do right now to develop specific inhibitors.

When did the idea come to you?

The day we heard the sequences were available and then we said, well maybe let's analyze the sequences and see if we could do anything. Now for HIV, if you make HR1, it doesn't work very well. For this virus the HR1 peptides do work.

Was it a team effort?

I told LinQi, let's go ahead and do this. And then he -- he's very good with the computer -- did the analytical work. There's a tendency to do just what people have done in HIV, and that's to make HR2 peptides. I think it was lucky that I said, "Let's not be too smart, let's go ahead and make HR1 and HR2." Now we're finding the HR1s are working better. So it's a little different from the HIV story.

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Richard Kao

Richard Kao
Richard Kao
Research Assistant Professor, Department of Microbiology, University of Hong Kong
May 10, 2003

What happened today?

What happened today is that after several days of incubation, this morning we got a chance to look at the cells, and we found out that some of the peptides actually can inhibit the virus. That means that with the peptides the virus cannot get into the cell, so that's extremely exciting for us.

You seem surprised.

Yeah, actually we were. We were very nervous over the past few days because of all those new drugs or peptides synthesized by David Ho and LinQi Zhang. We don't know whether they would have an effect or not, so basically you are waiting. So you're just building up, building up, building up. So today -- this morning -- is the moment of truth, and I'm very glad that actually some of the peptides worked out beautifully at this stage.

Illustration of a cell with and without an inhibitor

What does this result mean?

Today's result basically tells us that there will be a way -- a simple, very effective way -- that the virus can be blocked [from] getting into the cell in the first place. Hopefully in the near future, those peptides will be actually put into clinical trials and maybe the market, so that people suffering from SARS will not be killed by this virus.

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Emily Coven is an Interactive producer at KQED in San Francisco.