An Interview with Tony Fauci

25 Years of AIDS

Tony Fauc

Tony Fauci, MD, has been at the forefront of the global response to HIV/AIDS ever since the first cases were described 25 years ago. Among many achievements related to the pandemic, he was responsible for the early expansion of the US National Institutes of Health's (NIH) HIV research capacity and won plaudits from many for engaging with HIV treatment activists and fostering dialog with them in the mid 1980s.

After gaining his MD degree from Cornell University, New York, in 1966, Fauci has spent almost his entire career at the National Institute of Allergy and Infectious Diseases at the NIH. He has been director there since 1984 and currently oversees an annual budget of US$4.4 billion that is applied to HIV/AIDS, influenza, tuberculosis, malaria, and other infectious diseases. He is also a key advisor to the White House and Department of Health and Human Services on global AIDS issues and other emerging infectious disease threats such as pandemic influenza.

Despite these prominent leadership roles Fauci continues to run a productive research program as chief of the Laboratory of Immunoregulation. His work has contributed fundamental insights into how the human immune system interacts with the replication cycle of HIV, and his laboratory continues to focus on elucidating the nature of the immunopathogenic mechanisms of HIV infection. Fauci has also contributed significantly in other areas of human immunology, including developing effective therapies for the previously fatal diseases polyarteritis nodosa, Wegener's granulomatosis, and lymphomatoid granulomatosis.

Fauci spoke recently to IAVI Report Editor Simon Noble about 25 years of the pandemic and the outlook for AIDS vaccines.

This is the 25th year since HIV/AIDS was first medically recognized, and you've been closely involved since the very early days. How has this pandemic changed the public health landscape?

The implications and the impact of HIV/AIDS over the last 25 years have just been absolutely enormous-certainly, in the history of how diseases change paradigms, HIV/AIDS over the last 25 years stands very high among them. It has touched so many of the components of global public health-how we appreciate and respond to emerging new infections subsequent to HIV/AIDS, the role of constituency groups and how the research and public health agenda is set, the relationship between resources that are put into a particular arena and the results that one gets out of them. I'm referring specifically to the large infusion of research resources that have led to such striking advances, despite the fact that 25 years later we still have a long way to go with regard to the epidemic.

You've acknowledged that treatment activists were hugely important in the development of effective antiretrovirals and gaining attention for the epidemic generally. Why do you think there is not now an analogous constituency actively advocating for HIV prevention efforts?

HIV/AIDS was unique, because for all the great killers in society-heart disease, lung disease, cancer-there have been a number of therapeutic interventions for a long time, and research and clinical trials in those diseases are aimed at developing improved therapies. The unique nature of the activism and the response of the research, public health, and regulatory community was that at the time there was virtually no recourse for HIV-infected individuals. There was no therapy. That was a very unique situation, to have a disease evolving while you're trying to do clinical trials and trying to get people to pay attention to the development of therapeutics at a time when there was no therapy.

So there had to be a delicate balance between doing a proper clinical trial to get the data required at the same time that you're sensitive to the needs of the community and people who are afflicted with the disease. That led to a number of things, including the parallel track that I was involved with, to allow clinical trials to proceed in a very well organized, precise way to get data at the same time as you make the drug available to those who, for one reason or other, cannot get into a clinical trial. So the compelling, urgent nature of the situation was very obvious to everyone when you have a deadly disease with no treatment.

Now, the situation with prevention is just as compelling, because it's just as important to prevent people from getting infected as it is to treat people who are infected; they should go hand in hand. And yet we have not seen as uniform a move towards the prevention measures that are necessary. Activists are involved in prevention, but it's such a complex issue because there are so many societal, traditional, cultural issues that go into the kind of prevention that will work for a particular region of the world. Take Sub-Saharan Africa: the whole issue of prevention is not just, 'avoid exposure to infection,' the situation there is very much steeped in the lack of empowerment for women and their inability to take into their own hands what needs to be done to protect themselves. That's very different from getting a gay population in a Western, developed nation to realize that despite the fact that there are adequate, even very good, therapies right now, it's still a very bad thing to get infected. In some segments of society in which the infection rate was going down and down, now it's starting to rebound, and the likely reason for that is the general impression-very, very incorrect-that to get infected is not really a big deal. It is a big deal.

It's also much tougher to get people galvanized about prevention when they're not infected. During the early days when activism was born, predominantly among the gay population, it was people who were fighting for their own lives. If you're not infected, you don't perceive it as fighting for your own life.

So beside the scientific challenge of developing a vaccine, one of the biggest challenges that we still face is that it's equally as compelling and difficult to implement the other preventive measures that we need.

So is more sociological research required?

I think that we certainly could use more but it's a very frustrating field, because very knowledgeable and scholarly people in the area of sociology and behavior have emphasized that there's a big gap between educating people and changing their behavior. For instance, traditionally, over centuries, women have been disempowered-how do you change that, and quickly? The only hope for that in my mind is real, strong leadership from national politicians, be that the presidents, the prime ministers, the health ministers. Obviously, you need both grassroots and leadership from the top, but the leadership needs to step up to the plate and really make it very clear to their citizens that there needs to be some dramatic changes in how their society looks upon the relationship between men and women.

CHAVI was granted recently. How was CHAVI initially envisaged within the NIH, and what are your hopes for it?

Despite the fact that there are a lot of very smart people and a lot of resources applied, the obstacle to an HIV vaccine is still a scientific one. There are some unique characteristics of HIV that relate directly to our inability, at this point, to develop a vaccine. The most important is that we do not know what a protective immune response would be because, astoundingly, there isn't a single documented case of anybody who has developed an established HIV infection and then spontaneously eradicated the virus. That tells us something very ominous. But the only way to determine the correlates of protective immunity is to specifically dissect out the exact nature of the immune response, what the holes are, what the stumbling blocks are, and what we think we can do to induce an adequate immune response with a vaccine.

As part of the Vaccine Enterprise, the NIH felt that we would take the first step towards encouraging others, because in the document that Rick Klausner, I and others wrote in Science (300, 2036, 2003) we said we need several centers of excellence in vaccine research, each covering a particular component that is a major gap in our knowledge regarding an HIV vaccine. Clearly, one of those is immunology.

So I decided to put out a request for proposals for what we would call a center for HIV/AIDS vaccine immunology, hence CHAVI. It was a very robust competition. The principal investigator who scored highest in the competition is Barton Haynes, from Duke University, and his team is putting together a program that we hope will answer some of those very important questions related to the immune system and its response to HIV/AIDS. They have some very good people involved, and I think that will get us another step closer to developing an HIV vaccine.

So is CHAVI more a matter of extra funding, or will it be a truly new way of conducting research?

It'll be both. It's certainly a significant increase in resources, because the first-year funding was something like US$15 million and then it stands to get up to $40-50 million per year subsequently, but it's also a new way of looking at it, modeled on multiple groups synergizing with each other to answer some specific questions. It has a critical mass phenomenon.

So do you think the NIH can do it all?

No, I don't think the NIH can or should do it all. There needs to be a lot of input from industry, a lot of input from NGOs, a lot of input from other nations who fund through their own mechanisms, the nations in the Western world and in the developing world. A resounding no to the question of NIH doing it all alone. And I think one of the major partners in the development of a vaccine is industry, obviously.

So how can the biopharmaceutical industry be encouraged to engage more fully in AIDS vaccine research? Do you think advance market commitments and other such financial incentives will be useful?

Yes, those are mechanisms that can help. In discussions that I've had with some of my colleagues in the pharmaceutical industry, particularly some of the CEOs who will remain unnamed, they've said, 'All you have to do is just give us a wedge, open up a scientific window for us, and we'll jump all over it.' Some companies, like Merck and others, they're committed and in for the duration, from both scientific and developmental standpoints. But we really need to continue to engage them and, as scientists, clarify and elucidate some of those scientific barriers that still exist; then it will be easier for the pharmaceutical companies to come in when they see enough scientific basis to take the risk to get involved in the vaccine field.

Do you think that organizations will continue with their traditional roles-fundamental research done by academia and government institutes, and the development process taken over by the biopharmaceutical sector?

No, I think it's going to be more of a sharing of both, because we're seeing companies like Merck and others doing research as well as the developmental process, and then other models, particularly the NIAID Vaccine Research Center (VRC) with Gary Nabel, its director, getting into the actual vaccine development process. With the VRC we wanted to have, under one roof and within one organizational structure, the capability of doing everything, from fundamental research to the development of pilot lots and the institution and execution of a clinical trial. So I don't think there's a further Balkanization of roles, I think it's more of a sharing of roles now.

So do you subscribe to this idea of the industrial research model?

You've got to be careful when you say "industrial research" because industry, with few exceptions, doesn't do undifferentiated, fundamental research. They have a concept that's already proven and then they develop something from that. That is very important to get to where we want to be with a vaccine but we've got to be real careful that we don't declare a basic science victory and say, 'Now we just need to develop.' There are still fundamental questions that we really need to address, and that may not be able to be done in an industrial, pharmaceutical company environment.

If it's all we can achieve with a first generation AIDS vaccine, do you think that a partially effective vaccine that protects from disease rather than infection will be acceptable in different countries?

That is an important issue that doesn't have a clear-cut answer. It really is going to depend on where we are. I think the acceptance of a partially effective vaccine will be much greater in those countries that are just being devastated by infection, where you're seeing the very fiber of society crumbling under the burden of HIV.

At this point in the scientific endeavor, which do you think will advance the AIDS vaccine field fastest: increased clinical trial capacity to test vaccine candidates in humans, or more fundamental research capacity, particularly nonhuman primate model research?

I think there needs to be a balance between fundamental research and empiricism, and I've been saying that for so many years. You don't want to go overboard on the empiricism; there are enough scientific concepts that need to be elucidated. I think you will ultimately have to bite the bullet and empirically go into a clinical trial once you have a concept that's firm enough to warrant it; however, we have a lot of mileage to go in understanding some of the fundamental pathogenesis and correlates of immunity in HIV infection. You cannot jump into a clinical trial with virtually any candidate that happens to come your way.

So what do you make of the current heightened interest in innate immunity and the links with adaptive immunity?

I think that's terrific. It's the way the discipline of immunology was going anyway, and there's now a very fertile arena in HIV/AIDS research. There's a lot of funding going into innate immunity now, more over the last couple of years than in the previous decade.

Do you think innate immunity has most potential for manipulation by a vaccine directly, or in an adjuvant capacity?

I think both but, practically speaking, in the adjuvant capacity. HIV research is helping us explain what we never knew about adjuvants and how they work, to understand the molecular mechanisms of how innate immunity leads into adaptive immunity, and how perhaps we can actually amplify the immune response by utilizing some of the molecules, mechanisms, and signaling pathways that innate immunity uses. Now that we've got that off the ground, we need to design adjuvants to actually utilize what we now know about that exquisite interaction between innate and adaptive immunity.

There's also now a renewed interest in mucosal immunity since it's likely a vaccine will have to be effective there. Mucosal surfaces aren't easy to work with; sampling, particularly in humans, is difficult, time consuming, and costly, and it's difficult to recruit volunteers for such studies. How do you think we can work with that?

I remember meetings I had 15 to 20 years ago with mucosal immunologists, trying to get them involved in HIV research. Logistically, it's just a tough area of study. I think that's one of the big gaps that we have not adequately filled and I'm disappointed in that. We've really got to get them more involved.

So how can new talent, particularly established experts in other fields, be encouraged to enter into AIDS vaccine research?

By continuing to do what we're doing, namely having conferences and workshops that try to bring people together. Obviously, funding is the greatest way to encourage people. We've done that and there has been disproportionately greater funding for HIV/AIDS compared to other areas, which I think was appropriate. We haven't succeeded as much as we wanted but we've made some steps in getting those people involved. The problem is now, with the funding crunches at the NIH, with everything essentially being flat, there's not a lot of new money to put into new areas to stimulate things, so that's going to make it more difficult from a funding standpoint.

How can young investigators be encouraged to enter into AIDS vaccine research?

We've just got to encourage them, and emphasize that it's a very interesting field and the payoff is big-we're dealing with a global public health catastrophe of enormous proportions; therefore, not only is it exciting science but look at what you can accomplish.

Are you disappointed in the progress we've made with the antibody component of a vaccine?

Yes, of course. We have good people working on it and we are now finally defining the conformational issues involved in the induction of antibodies that would be cross-reacting and neutralizing against primary isolates. But we are certainly not where we want to be and this is still one of the big enigmas of HIV vaccinology. There's a lot of focus on cell-mediated immunity, T-cell based vaccines, but we will not prevent HIV infection unless we get a vaccine that will elicit cross-reacting neutralizing antibody against multiple isolates. We may get a vaccine that blunts the progression of disease, but we will not have a vaccine that prevents infection unless we crack the antibody enigma.

You've been director of NIAID since 1984, at the very beginning of the HIV/AIDS pandemic. How has your role changed in that time?

It's been a very interesting and important evolution in my own life, professionally and personally. I was a host-defense, infectious-disease immunologist in 1981 and I had already been a senior investigator at the NIH for nine years, dissecting out the immune system. My lab, long before HIV, was called the Laboratory of Immunoregulation.

When HIV came along I essentially completely turned my lab around and started studying the small group of gay men with GRIDS, gay-related immunodeficiency syndrome, as it was known then. Literally, from the very first reading of that June 5th, 1981 Morbidity and Mortality Weekly Report, I was fascinated by the disease I've been studying ever since. I was asked to be the director of NIAID in 1984 and one of the reasons I took the position was that I felt I could have a much broader impact on a number of fields, including HIV. One of the first things I did was to ask for an extraordinarily large increase in our funding, and I took the chance of getting into all the difficulties you do when you ask for funding, that is they'll tell you to implement your expanded program and they won't give you the money.

Fortunately for me, the Administration and the Congress did actually give us a considerable amount of new money. What I've seen evolve over the last 22 years is really one of the most extraordinary scientific odysseys imaginable. We've seen the evolution of a brand new disease that has already taken its place in the history of civilization as one of the most catastrophic public health events ever. For that to be evolving right before you as you're trying to do something about it is, in some respects, a frightening concept, but is also a phenomenal opportunity to do good for society.

That's the way I look at it-being in a certain place at a certain time in history, my whole career training in infectious diseases and immunology, and then all of a sudden along comes a disease that's an infectious disease of the immune system, that has already infected 60 million people and killed 25 million more people. To me, that's pretty heavy stuff.

So what is the secret to your longevity as director of this prominent NIH institute?

Be consistent, be honest, and work hard. You've got to stick by your principles. I've been through a lot of battles-with Congress, with Administrations, with constituencies. I think if you're just honest and consistent and fair, and let the science and the public health issues drive what you do, then it works. I think that's really the secret of it.