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Jeremy Carver on the International Consortium on Anti-Virals and the Role of Proteomics in Fighting Viral Diseases

Jeremy Carver
CEO and chief scientific officer
International Consortium on

At A Glance

Name: Jeremy Carver

Position: CEO and chief scientific officer of the International Consortium on Anti-Virals.

Background: Co-founder, president, CEO and chief scientific officer of GlycoDesign, 1994-2002.

Associate dean of basic science in the University of Toronto's faculty of medicine, 1989-1992; Professor in the University of Toronto's faculty of medicine, 1968-1994.

Postdoc in Rex Richards' laboratory, Oxford University, 1966-1968.

PhD in biophysics, Elkan Blout's laboratory, Harvard University, 1961-1966.

Biotech consultant Jeremy Carver is currently trying to raise $75 million to launch the International Consortium of Antivirals, a non-profit company that will work on finding vaccines and therapeutics for various viral diseases, including influenza, SARS, West Nile virus, and HIV (see ProteoMonitor 5/20/2005). ProteoMonitor decided to talk with Carver this week to find out about his vision for ICAV, and his opinion on the role that proteomics can play in fighting viral diseases.

What is your research background, and what have you been doing with the International Consortium on Anti-Virals?

In my academic career I was an NMR spectroscopist. I did 3D structures of carbohydrates and their interactions with proteins, so I was a structural glycobiologist, you might say. Out of that work, a group of us started a biotech company because we felt there was a future for inhibitors of glycosylation as potential drugs in a number of situations, particularly cancer and inflammation and infectious disease. So in 1994 I left the university and started a biotech company and ran that for eight years. It was called Glyco Design. The focus was on designing drugs to inhibit this glycosylation pathway. By the time I left we had Phase II clinical trials in cancer and a Phase I clinical trial in cardiovascular disease, and a number of partnerships.

More recently, I've been involved with this International Consortium on Anti-Virals. Needless to say, one of the platforms we're exploiting is inhibitors of glycosylation, but there are many others. There is a proteomics component. We're really trying to look for proteins involved in host responses to viral infection as potential targets, as well as trying to understand all the functions of the viral proteome, because there are clearly open reading frames for which we don't know the function, and they may be important for the way in which viruses take over cellular metabolism machinery.

But most of the effort at ICAV is pretty focused on a limited number of targets that have already been identified. One of the major subsets is the proteases — both the virally encoded proteases and the host proteases that are utilized by the virus as part of its infectious cycle. There's a broad range of viruses, particularly the enveloped viruses — the ones that have membranes around them and viral glycoproteins sitting in that membrane — they use human enzymes to cleave what's essentially their receptor.

For example on influenza, there's a molecule called hemaglutin, which is the molecule that binds to the sialic acid on the surface of the mammalian cell. The hemaglutin binds, but in order to get fusion of the viral membrane with the host cell membrane, you have to cleave the hemaglutin and trigger a conformational change to get fusion. The cleavage of the hemaglutin is performed by a human enzyme in the converase family, usually furin. So inhibitors of furin can block that process and prevent viral entry.

It turns out that influenza's not the only virus that does that. The same mechanism is used by unrelated viruses like HIV, West Nile, hepatitis C. So by developing inhibitors that target this host function, you have the potential of getting what we call enhanced spectrum antivirals. We hesitate to use the term broad spectrum, but in parallel to broad spectrum antibiotics, one could talk about broad spectrum antivirals. In other words, molecules that work on more than one kind of virus.

The glycosylation pathway is another host function that the virus uses. The virus has no mechanism for putting carbohydrates onto its glycoproteins — it uses the host's mechanism. And in a number of situations, it's essential for the correct assembly of the viral particle for the virus to get the glycosylation right. So if you interfere with the glycosylation, you can prevent the mature infectious particles from being introduced. All viruses use the host cellular glycosylation machinery. Many viruses are vulnerable if you interfere with that.

Given that there are common ways that viruses infect cells, do you think it's still necessary to have large-scale efforts, like the ones for SARS, to characterize the 3D structure and function of every protein?

I think it is because we know so little about the interaction between the virus and the human cell. In the last few years, we've learned about proteins that the virus produces to shut down the interferon response. Interferon response is the natural defense mechanism of the cell for combating viral infection, but the virus has mechanisms for shutting down the interferon response. So again, that's a whole other set of targets. If you could interfere with the ability of the viral protein to shut down the interferon response, you could get natural clearance of the virally infected cell.

The whole story is that the virus has been in this constant dynamic evolution with its host. Over the years, the host develops ways of defeating the virus. The virus then develops ways of defeating the host. There's layers of defense mechanisms and counter-defense mechanisms, and that's where proteomics comes in — in mapping that all out. It's clear that if you take a proteomics approach, you can look at the dynamic interactions that go on in the cell, because when we inhibit a single target, there's a cascading effect on all sorts of other metabolic activity in the cell. We need to understand that in order to understand side effects. This kind of silver bullet — hitting a well-defined target as a way of controlling a disease — is very short sighted. Every time we interfere with a particular cellular process, there's a subtle cascading effect on a whole range of other cellular processes. That's the sort of thing that we can pick up with a proteomic approach. We can pick up some of the more obscure side effects, and understand the mechanisms behind the side effect.

So studying the proteome before and after infection or vaccination would help to understand the mechanisms of the virus?

And after treatment as well. If you take an infected cell and treat it with an anti-viral, and you look at the impact on the proteome, then you can explain some of the complications that you see that you wouldn't necessarily expect.

So that's one proteomic approach for looking at viruses. Another approach is to look at the 3D structure and function of every viral protein. Are there other ways of using proteomics to study viral diseases?

Well those are the major ones that I'm involved with. In Europe, there's an organization called Vizier — it's an EU funded network — it set itself an objective to obtain the structures of all of the proteins encoded by all of the RNA viruses. Well, they haven't gotten very far, but it was seen as an endeavor that was worthwhile. And it's really because there are many ORFs in the viral genome for which we do not yet have a function. And until we do, we won't really have exhausted all the possibilities with respect to targets.

Another thing that 3D structures do for you is they often give you suggestions as to what the function might be. There are proteins that have very little resemblance between their amino acid sequences on the primary level, but have identical folds and perform very similar functions. So when you see the 3D function, you can say, 'Oh, that's obviously a serine protease,' or whatever.

Also, there's a guy at the University of British Columbia — John Schrader — he's developed a method of isolating antibody-producing cells from convalescent patients. So take a patient who's had a viral infection and is recovering — that suggests that they've mounted an adequate immune response — take a blood sample and look at the antibody-producing cells and screen them to find the ones that have the highest neutralizing activity. And then he has a technique for cloning that single cell, so essentially you have a monoclonal antibody. It's a monoclonal antibody that was produced by the patient in response to the infectious agent, that you already know has neutralizing activity. So you don't even need to know what the epitope is, it's something that can be used therapeutically. It's a great black-box approach for responding to unknown infectious agents, such as SARS was.

I think there are in fact companies in Europe that are trying to exploit that approach, or variations on that approach.

We're always concerned about the emergence of novel viruses. The broader the spectrum of our potential antivirals, the better for first response situations, where somebody's coming in with respiratory distress and we don't know what the virus is.

As an example here in Toronto, it took them 10 days or two weeks to identify that there was a Legionella outbreak. So you'd love to have something that would work regardless, and in that case it was OK, because they were treating with agents that would work for Legionella, but whether it's Legionella [bacteria] or SARS or another virus, you'd love to be able to say that anyone who comes in with a bad cough and high fever should get this drug because it'll hit all the viruses that can possibly be causing those symptoms.

Do you think it's necessary to develop better diagnostics for viral infections?

Very much so, and it goes a little further than that even. We're never infected with just one pure genotype of virus. There's always a mixture, and certainly during infection in the body, that mixture becomes more heterogeneous. So it's not just being able to detect what virus it is, it's also being able to get some sort of profile on the genetic make-up of the mix of viruses that a patient is infected with.

I'm thinking as I say this of a very recent paper that came out Nature looking at a young woman in Vietnam who became infected with the H5N1 virus. And even though she was on a prophylactic dose of Tamiflu, and when she became sick was put on a much higher dose and recovered — in looking at her viral isolate before she went on the higher dose of Tamiflu, a group in Japan was able to clone out 10 different viral clones, and one of them was totally resistant to Tamiflu. It was over 1,000-fold more resistant than the sensitive strain. And it had accumulated seven or eight mutations.

So it would be marvelous to have technology that would allow one to instantly profile the genotypes of viruses that are infecting a patient, and not simply use an antibody response to classify generally a viral infection as an H5N1 instead of an H3N2.

There are levels of sophistication in diagnosis that are highly desirable, but there are also some very fundamental practical things. Like the developing world, where there isn't a lot of infrastructure, you need to be able have very simple diagnostic tools that can identify the infectious agent very rapidly and allow the proper treatment to be applied.

How many people would you say there are that are working on proteomics and viruses? Is it a pretty rare way to study viruses?

I really don't have a way of telling. I don't think there's a great deal of activity. I know there isn't a great activity in Canada, but that's not saying too much. I suspect that most of the major pharmaceutical companies are using proteomics approaches — the ones that are interested in anti-virals, because not everyone is.

Would you say it's difficult to set up collaborations between proteomics researchers, virologists, and clinicians?

Well, yes. And containment is one of the issues. A number of centers I know here in Canada have talked about setting up full proteomics capabilities under containment conditions. The whole problem when you're trying to grow viruses is you have to do it under containment because they're human pathogens. And then if you want to do proteomics on infected cells, you don't really want those in your mass spectrometer. So the thought of dedicating mass spectrometers in containment suites is the direction that that's going, but that's very expensive, and of course you've got to be certified for the viruses that you want to look at. It's a long and tedious process, but there are places that are doing that, that are going to those kind of lengths.

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