The Future of AIDS Research
An Interview with Dr. Mario Stevenson
October 10, 2006— Mario Stevenson, Ph.D., is the newly appointed chairman of amfAR’s Research and Scientific Advisory Committees. A native Scot, Dr. Stevenson received his Ph.D. from the University of Strathclyde, Glasgow. In 1984, he moved to the United States to pursue his scientific interest in viruses and has since become a leader in AIDS research. Now director of the Center for AIDS Research and professor of molecular medicine at the University of Massachusetts Medical School, Dr. Stevenson’s primary area of research involves studying how viruses such as HIV cause disease. In his challenging new volunteer role at amfAR, Dr. Stevenson will help shape the Foundation’s research priorities in the years to come. amfAR’s Dr. Rowena Johnston, director of research, spoke with him about what those priorities are most likely to be.
amfAR: One of your first tasks as chairman of amfAR’s Research Committee was to convene a think tank. What was its purpose?
Dr. Mario Stevenson: The think tanks are designed to bring together a group of individuals to come up with a strategy to support a particular problem in the field. The problem that we’re facing right now is, why do the available drugs not cure AIDS? Now it’s a simple question, but the answer is anything but simple. We have antiretroviral agents that are incredibly effective at suppressing HIV. Unfortunately, the drugs are failing in many individuals because they’re toxic, and the virus becomes resistant to the drugs in some individuals, meaning that they are no longer effective. So about 25 percent of patients who are on these drugs eventually fail therapy. The drugs are a stopgap measure. They’re not a long-term solution.
So if the drugs are so capable of suppressing the virus, why don’t they eradicate it completely? One possibility is that the virus has either found a niche—a compartment—in the body where it’s protected from the drug, or that the virus has somehow become dormant so that the drugs don’t do anything. When the drugs are removed, the virus comes back again.
Despite all the research that’s been done in the past, we still don’t know the answer to those questions. The think tank participants identified the ways this question could be addressed by amfAR’s research program, and then those discussions became the basis for our latest research request for proposals.
amfAR: The request for proposals (RFP) is called “Exploring the Potential for HIV Eradication.” Do you think this reflects a new optimism that eradication may be possible?
Stevenson: I think the issue of eradication has been played with by a number of individuals, and people feel very strongly one way or the other. What a burgeoning body of literature is supporting is that perhaps the reason HIV is resisting therapy is because it’s actually found a niche, it’s found a way to protect itself. But there is no really definitive evidence for that. So the first thing you have to do, if you want to eradicate the virus, is identify how it’s able to survive in the face of comprehensive therapy. Once you know the answer to that question, then you can come up with better strategies to achieve eradication.
This will lay the groundwork for more ambitious studies that may lead to therapeutic strategies that actually do achieve eradication. Now if you want to believe in eradication, you have to be a little bit of an optimist. Obviously, I’m one of the optimists.
amfAR: What other areas of research do you think are important or hold a lot of promise right now?
Stevenson: I think one of the subjects of a recent amfAR RFP was particularly important: the area of cellular defenses.
Humans, it turns out, are a very hostile environment for viruses like HIV. Our cells have proteins that carry out natural functions in the cell. Some of these proteins have a very toxic effect on HIV.
So if our bodies carry these natural defenses that protect us against HIV, why do we get infected? The virus has evolved a strategy to protect itself. So if we can find a way to foil the virus’s defense mechanisms, then we would render it sensitive to the human body’s natural defenses and hopefully make us resistant to HIV. If we can mobilize our natural defenses, I think we’d have a very powerful protection against HIV. And if I were betting the mortgage, I’d put my money on the natural cellular defenses rather than a vaccine strategy.
amfAR: Do you see that in the form of a therapeutic strategy?
Stevenson: Right. If we could come up with small molecules that prevent the ability of the virus to counteract these cellular defenses, then the virus would be rendered susceptible to our body’s natural defenses. We would be able to protect ourselves from HIV. I should emphasize that these cellular defenses are incredibly potent.
amfAR: They’re more potent than any vaccine currently used to prevent other diseases?
Stevenson: Right. The main weakness in a vaccine strategy is that the virus is incredibly variable. Because HIV is continually changing its structure, the immune system can’t get a fix on it. The virus is continually evolving to avoid recognition by the immune system.
In contrast, these natural defenses are oblivious to the variability of the virus. They attack the virus regardless of what type of HIV it is. So this sort of strategy would work against all HIV variants.
amfAR: Last September you agreed to chair amfAR’s Research Committee and the Scientific Advisory Committee. What made you decide you wanted to accept?
Stevenson: I’m probably one of amfAR’s biggest fans. I got my first grant through amfAR in 1987. At the time I was trying to transition to being an independent investigator. It’s a stage where you’re trying to establish your laboratory, teach, write grants, and it’s also the most difficult time in terms of finding funding for your research. So I applied to amfAR and got funded, and that really set me off on an independent career in HIV. Two years later, I was able to apply for funding from the National Institutes of Health (NIH). I owe amfAR a lot for that, and I feel that I have a commitment to help amfAR support other young investigators and to fill a void that’s been left by federal agencies in terms of supporting young investigators.
amfAR: Do you think it’s equally difficult now for young investigators to get funding? Have things changed?
Stevenson: Right now it’s incredibly difficult for young investigators to find funding. When I was establishing my career as a young investigator, the NIH had a mechanism to support young investigators. It was called a First Investigator Award. And it was specifically for those who were applying for their first NIH grant. Because of this, those investigators didn’t have to compete with established investigators.
A number of years ago, the NIH phased that program out and young investigators had to compete with established investigators. As a result, it’s not a level playing field.
At the NIH now, one in every eight grants gets funded, meaning that young investigators really have very little chance of getting funded, because the established investigators are competing hard for the little money that’s there. Rather than thinking of the science and doing the science, young investigators are spending all their time chasing up ways to raise money. And it’s not unusual for people to have to wait a year or more before they actually receive funding they’ve applied for.
amfAR: How does amfAR help fill that need now?
Stevenson: amfAR supports young investigators through its research fellowship program. Plus, amfAR has a quick turnaround time. If an investigator needs to have their research funded, they can’t wait a year, a year and a half. By then, the field has moved on and the research is out of date.
What amfAR is doing is trying to prioritize the most important issues. And that can be a tall order, because the field is changing so rapidly. What is hot today will be history in six months. amfAR is well placed because it’s so mobile, because it’s able to respond and grant funding quickly. It can really keep zeroing in on the most important issues as they evolve.
amfAR: Are there other way in which amfAR supports young researchers?
Stevenson: Yes. It’s not enough just to give an investigator money, particularly a young investigator, because at some point in time that investigator has to be presenting results to an audience of peers. And ultimately the investigator gets a wake-up call when they find that their research is not well received, or they submit an application for a more ambitious grant and they find that the reviewers don’t like the direction they are taking.
In other words, there is no mentoring of young investigators to help them identify the most important issues in the field, and to show them how to go for more ambitious federal funding. By requesting that grantees go to meetings and participate in some of the workshops at these meetings, amfAR is helping to start them off on the right foot. You’re preparing them for a tough career as an independent scientist.
amfAR: In a recent article calling for more spending on research, someone made the point that people who suffer from various diseases are concerned mostly with “the fix.” I like to think that amfAR is also concerned largely with the fix—the solution. We understand that we need to know details in order to get there, but the fix is clearly our goal. Would you agree?
Stevenson: In theory I agree with that, but in reality you have to have research in a wider theater. We need to have the serendipity element. Scientists have to be allowed free rein to also create conditions for accidental breakthroughs. They don’t happen by design. They happen because a lot of good scientists are pursuing different ideas and those findings come together to form a new solution.