In 1993, for example, Fauci and colleagues published a paper in Nature describing viral activity in lymphoid tissue during the disease's so-called "latent" stage (see G. Pantaleo, et al., Nature, 362:355, 1993). The paper, which was a mainstay in Science Watch's biology Top Ten lists during 1994 and 1995, has now been cited more than 500 times and stands as the most-cited paper of the last three years in AIDS research. As biology correspondent Jeremy Cherfas noted recently, the paper caused a major shift in the way researchers view the virus and helped to revitalize the entire field (see Science Watch, 7[2]:8, March/April 1996). More recently, Fauci reported encouraging results with the use of IL-2 for immune reconstitution of HIV-infected individuals. With over 32,000 citations to his work, Fauci is now the fifth most-cited scientist of the last 15 years.

   Outside the laboratory, as the government's point man on HIV research, Fauci is helping shape the government's AIDS research agenda.

   Fauci received his M.D. degree from Cornell University Medical College in 1966 and then completed an internship and residency at Cornell Medical Center in New York City. In 1968, Dr. Fauci came to the NIH as a clinical associate in the Laboratory of Clinical Investigation at the NIAID. In 1974, he became Head of the Clinical Physiology Section, LCI, and in 1977, he was appointed Deputy Clinical Director of NIAID. He was appointed Chief of the Laboratory of Immunoregulation in 1980 and was named Director of the NIAID in 1984. Science Watch correspondent Paul Kefalides met with Fauci at his offices in the NIH in Bethesda, Maryland.

            How did you first become involved in HIV research?

   Fauci: It was an interesting evolution. Fate, in essence, made a lot of things come together. I remember very clearly in the summer of 1981 when I got wind through the Morbidity and Mortality Weekly Report of these unusual cases of immunodeficiencies in gay men. I didn't know what it was, but it somehow suggested an infectious disease to me. As we started to learn more about the fact that there seemed to be a selective CD4 positive T-cell defect, a number of people started thinking, well, maybe this is some sort of aberrant retrovirus similar to HTLV-1. But I was not a virologist; I decided to approach this disease from the immunologic and immunopathogenic standpoint. Over the next three years, I converted most of my laboratory to the pursuit of HIV research. By the mid-1980s, once we had the virus in hand, my entire section of the laboratory became involved in research on the immuno-pathogenic mechanisms of HIV disease.

            In reviewing your publications, it's clear that you were able to learn a great deal about HIV pathogenesis even before the virus was identified.

   Fauci: Absolutely. For example, we had done some work on the role of aberrant hyperactivity of B-cells in autoimmune diseases, so we decided to check for any kind of B-cell defect. We found, to our extraordinary surprise, that there was an aberrant hyperactivity--a paradoxical hyperactivity of one limb of the immune response concurrently with a defect in the T-cell limb of the immune response. We demonstrated that there was a polyclonal activation of B-cells, and that was the first paper that we published in the New England Journal of Medicine in 1983. We then started looking at some of the T-cell defects, and we were the first to demonstrate, back in 1985, that it was an antigen-specific defect that was much more pronounced than a mitogen-induced defect. So cells could not respond to certain antigens and yet they could be triggered by mitogens. This work was a natural evolution of what I was doing in the 1970s on immune-system regulation.

            In what ways did this early research provide a groundwork for our understanding of HIV?

   Fauci: One of the questions I asked back then was, since the virus and the disease seem to be active chronically and it's possible to get the virus to propagate in culture but it needs a cell with an activated phenotype--that is, a cell that is turned on a bit--then why is it that people with HIV disease have chronic disease that goes on and on with cells in a perpetual state of activation? How is the virus able to activate the cell and stay at a state where it continually, but at a very low level, expresses virus? The thought occurred to me, maybe it's the normal immunoregulatory cytokines that do it. So we developed our cell line, the ACH-2 and the U-1 cell lines, and we demonstrated that cytokines like TNF-1 and IL-1[beta] and IL-6 were able to induce the expression of HIV in chronically and latently infected cells. We then demonstrated the basis of this at the molecular level.
   This led to a number of our studies on the cytokine network. Thanks to PCR techniques, we now know that the virus can essentially replicate throughout the course of HIV disease. So the theory that we originally put forth in the mid-1980s--that cytokines are responsible for this--fits perfectly with what researchers are finding. It is the normal milieu of lymphoid tissue that is responsible for the constant propagation of virus. This led us to compare the quantity of virus in peripheral blood to that in lymph nodes. When we looked at peripheral blood lines of these cells, using in situ hybridization or RNA and DNA PCR, we found that very few were infected. So we said, why don't we take a look at the lymph nodes? That's when we switched our lab over to looking at lymphoid tissue.

            That was the point at which you focused on lymph nodes, and in so doing redefined the notion that HIV can be a latent infection?

   Fauci: Yes. In our first paper on this topic, we noted the extraordinary situation where all this virus was clustered in the lymph node at a time when one would assume that there was not a lot of virus in the blood. Then we did a prospective study, taking three groups of people and designating them either early, intermediate, or advanced, depending on the degree of depletion of their CD4 cells. We looked simultaneously at each person's blood and lymph node to determine, at a time when there is very little virus in the blood, how much virus resides in the lymph node. That's the paper that first demonstrated that even very early in disease, there is always active virus replication and it occurs in the lymph node.
   This paper really caused researchers to rethink what latency meant. Although many patients may be clinically latent, meaning they are feeling well, we in the field have probably made the wrong assumption that this equates with disease latency and microbiological latency. We know now that there is never disease latency except in the case of the long-term non-progressors. Nor is there ever microbiological latency--with very few, rare exceptions.

            How would you evaluate the strategies for fighting HIV disease?

   Fauci: Among the numerous strategies, the one that must pervade everything is suppression of the virus. There is also immunological enhancement and expansion of the T-cell repertoire by IL-2. That really should only be done within the context of an antiviral so that any induction of expression of the virus by IL-2 would be blunted by the antiviral. So I would never recommend that type of immune-enhancing or repertoire-expanding approach without concomitantly having an antiviral on board. But having said that, look at the different categorizations: there's expansion of T-cell repertoire by IL-2, there's direct antiretrovirals like protease inhibitors and the reverse transcriptase inhibitors. Then there are other approaches that have been more controversial, such as vaccinating somebody who is already infected. As you know, there is considerable discussion as to whether or not such a procedure is even relevant. My intuition is that it isn't, but, being a scientist, I will remain open and see what the data show.

            How do you think AIDS has changed the drug approval process in the United States? Some worry that the values of the scientific method are being sacrificed to fast-track drugs.

   Fauci: It's a controversial subject. I don't think one can say it is cut and dried. Because of the compelling nature of the epidemic and because we had no really good drugs available early in the epidemic, the activist community played a major role in raising consciousness of the need to have constituencies empowered to choose whether they want to take a chance of having a drug available to them that has not yet been proven by the classic seven-year method. Many patients said, "I don't have seven years. I may have one or two years, so I would like to make the decision that I would be willing to take the chance." That sentiment was the underpinning of the shift in philosophy for rapid approval and early availability, parallel track, and expanded availability of drugs. All of these things really fall under the rubric of getting the drugs out more quickly than we ordinarily did.
   Now, if you do that without compromising the science of the trial that would definitively determine if the drug worked, then that's fine. One of the difficulties you run into is once a drug becomes widely available, it becomes difficult to do the type of trial that would definitively get the answer, because people won't want to be in a trial. They'll say, "I'll take my chance with the drug. Why do I, the patient, want to determine if this works versus that one?" When people are desperate, it gets very disordered. And consequently, people have argued that this has paradoxically slowed down the progress. I'm not so sure that is entirely correct. I think that if expanded access is done correctly within the context of ongoing clinical trials, then you can still get the solid scientific answers at the same time that you make the drug available to people who otherwise would not be qualified for the trial. That was what I put forward as a proponent of parallel-track expanded access. From the government side, I was the one who was pushing that.

            How does parallel track work?

   Fauci: You preserve the integrity of the clinical trial process but you make the drug available to people who wouldn't be able to get into a trial because of the advancement of their disease. That way, you're not detouring people on the way to the trial; you're just making something available to them at the same time that you are conducting a trial.

            Are there particular directions in HIV research that you think will earn generous funding?

   Fauci: Right now it's clear that understanding pathogenesis is key, and there is much more of a tilt towards understanding basic pathogenic mechanisms. Something you may not appreciate is that when Congress earmarks money, they can mandate directly in the language of the bill the type of studies that will be sponsored. Early on, we were mandated by Congress to put a lot of money into clinical trials because the constituencies felt they wanted to get access to these experimental drugs. Less attention than I wanted to see at the time was spent on basic fundamental research on pathogenesis. Now everyone is getting religion--everyone wants basic research on pathogenesis. But back in the mid-and late 1980s when I was testifying before Congress about the importance of doing fundamental research on pathogenesis, people were not looking on that with a very sympathetic eye. And now it has come full circle. Everyone is talking about pathogenesis.

            And, finally, can you tell us about your future plans?

   Fauci: My future is that I am totally committed to getting the answers to this AIDS problem. I am going to stick it out until we do. Maybe that's unrealistic. It may take more years than I have. I think we are going in the right direction in research now, such that I would be surprised if we do not have tangible improvements in the management of HIV-infected people and tangible advances in understanding pathogenesis in the next few years--to the point where we will have some solid strategies and solid projects implemented for the development of a vaccine and for combination drugs.

            Do you think a cure is more likely, or a therapy that renders HIV a non-lethal, non-disabling chronic illness?

   Fauci: I don't think there will be a cure, based on my experience with this virus and its ability to integrate and stay within the genome of a cell. I never say never. But I'm not expecting a cure. I'm expecting that we will have a combination of drugs that will render many people to be the functional equivalent of long-term non-progressors, so that you suppress the virus and they do fine. I also think that when we fine-tune the immunological reconstitution by expanding repertoires with IL-2 that we may be able to maintain people at 400-500 T-4 cells--much more stable than a precarious level around 200 T-4 cells. If you keep people at that stable level and suppress the virus, who knows how long you can keep them going? So when I discuss what I'm looking forward to, I'm not talking about walking out of here with a cure and a vaccine; I'm talking about having things under much better control than we have them right now.

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