|AIDScience Vol. 2, No. 18, September 2002|
|Broadly cross-reactive anti-HIV neutralizing antibodies:|
|A conversation with Robert Gallo|
|Robert Gallo is director of the Institute of Human Virology, University of Maryland Biotechnology Institute. Recent data published by his group showed that covalently cross-linked complexes of the HIV-1 surface envelope glycoprotein and CD4 elicited antibodies in rhesus macaques that were able to neutralize a wide range of primary HIV isolates, regardless of their subtype or coreceptor use. Roberto Fernandez-Larsson interviewed him for AIDScience during the 2002 International Meeting of the Institute of Human Virology held in Baltimore, September 9-13, 2002.|
[AIDScience] What are the most relevant things that have happened in your lab in the last 12 months?
[Robert Gallo] We have taken the gp120-CD4 complex [PubMed] [PubMed] to another stage of development for a preventive vaccine. We have a complex that is able to induce broad, neutralizing antibodies. We are able to get a very good, long-lasting titer. Eventually that titer is going to go down. However, you want a response right away when the virus enters the body.
The project is now at the level of a biotech company, and we are collaborating with the International AIDS Vaccine Initiative (IAVI). We will probably make a deal with IAVI to help carry this project to the next level as fast as we can.
Last year you told us about the Waterford Project (WP). Is the WP involved?
It is not. John Evans, who started the WP and donated half a million dollars of his own money, was never able to raise the big money, like IAVI. Evans has gracefully bowed out and is trying to do things to help IAVI.
Who came up with the CD4-gp120 complex project?
Anthony DeVico [PubMed] started it and independently by John Gershoni [PubMed], who was in my lab in 1988. Tim Fouts [PubMed] did the bulk of the work. Franco Celada [PubMed] was the first that was dealing with a structure like this, but for purposes other than a vaccine.
|Dr. Robert Gallo, director, Institute of Human Virology, University of Maryland Biotechnology Institute.|
Do you think virus escape mutants are still possible with a vaccine like this?
Anything is possible, but if you are protecting against the first step of the infection you have to fight against total prevention. It is theoretically possible let's say we have variants that combine with another receptor that is not included in the region of gp120 but we hope that the incidence will be very low.
Are there two camps in the HIV vaccine research community, those who favor a vaccine that promotes cell-mediated immunity and therapeutic vaccines, and those that favor a preventive vaccine that promotes neutralizing antibodies?
I would not look at it like that. Anybody with a brain bigger than a bird would agree that if you can get broadly reactive neutralizing antibodies that block entry completely you would be an idiot not to agree.
They may agree with the concept, however, they are working on something else.
The reason is because anything is possible. I also was involved in trying to get broadly reactive antibodies with HIV envelope: it does not work. That happened in the late 1980s; the field went into a depression. Then in the early 1990s, they thought maybe they could do this with cytotoxic T lymphocytes (CTL) and cell-mediated immunity (CMI), and ended up with good monkey data. We decided to stay with viral entry block not many people did. Now, the CTL-CMI people are worried because it looks bad. Suddenly, monkeys are breaking through.
How is the gp120-CD4 complex vaccine going to be delivered?
There are multiple possibilities and needs to be experimented: directly with protein, the DNA form, or our Salmonella DNA vaccine vector [PubMed] that can be delivered orally. First, we will probably go for direct protein or intramuscular DNA delivery.
What is the time frame for this vaccine?
I think the project will go to trials in about 20 months. It all depends on money I think we are going to get it.
Last year when we talked, your Tat vaccine [PubMed] was more in the forefront than this project...
Last year this project was in the planning and the in vitro stage. The results on Tat that we have been publishing recently are confirming a lot of the in vitro data, and we also have a little bit of monkey data. Aventis is already doing small therapeutic clinical trials in Europe. Our Institute has started therapeutic Tat vaccine trials in the U.S.
Can you foresee the Tat vaccine improving vaccines developed by other investigators?
Yes. Not everybody can explain this to you because it is complicated. Our view is that it is a very sensible therapeutic vaccine that needs large testing. It also makes sense to add it to a preventive vaccine. Let us say, for example, that our gp120-CD4 complex is a success, protecting experimental monkeys for a while. My prediction is that in humans the following would happen: vaccinated with the gp120-CD4 complex, the subjects become protected against infection, and therefore do not need any Tat vaccine. However, three years later, some of the vaccinated people have low titers. What is needed to boost these titers? Normally, to boost you would need exposure to the virus, but HIV rapidly down-modulates the CTL response through Tat. This is what we believe our hypothesis based on data, and we want to convince the Aventis group that they should also include it in their preventive vaccine strategy.
In the discussion that followed one of the presentations I heard you make a comment about highly active antiretroviral therapy (HAART) versus vaccines in Africa...
There are ethicists, and economists have joined them, that say that it is unethical if you do not use HAART in Africa. This inhibits new experimental developments that could be more practical for Africa. I cannot believe I do not care who tells me otherwise they are not going to have an immense problem. I think you should use HAART wherever it is possible, but for the bulk of Africa I do not believe you can follow people [in treatment] when you need an infrastructure that will cost you three times the cost of the drugs. I also think you will make massive drug-resistant strains. So, I would say, go ahead with drug treatments but do not stop people from initiating experimental approaches that could prove to be more practical. If Tat were helpful, why would you stop it? I also believe as do others that interferon alpha, which overproduces quickly after infection and especially in late HIV stages, is immunosuppressive. It would be easy, simple, and safe to vaccinate to reduce that overproduced level. We could give three injections per year something that anybody in the village can do.
If it worked, it would certainly be better than having millions of people take several pills a day...
Right, and it is nontoxic. Why should we do in Africa what we are doing in the U.S. or in Europe? It is ridiculous. I am not saying that one should not work hard if one can, for example in some of the major cities in Africa, but nobody is going to tell me that you are going to treat 70 million people or 50 or 60 million and follow them every day to make sure they are in compliance and do the viral analyses for mutants.
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