Office of NIH History
In Their Own Words: NIH Researchers Recall the Early Years of AIDS
Previous Page | Next Page (2 of 6) Transcripts  

Harden: Over the years you have continued the twin study. What else have you been able to learn from the twins?

Fauci: We have done a number of transplantations. We recently reported a series of sixteen to eighteen transplants from well donors to their HIV-infected twin brothers. First of all, the transplants have not been dramatically successful, so two things were learned from that. We learned that in order to be able to reconstitute immunity we have to suppress virus replication adequately, because the virus will only re-infect the transplanted cells or the transfused cells.

The other thing that we learned, and this is what we are very actively working on now, is that we have a number of lines of evidence to indicate that the microenvironment of the immune system is destroyed by HIV, not just the CD4positive cells. We do not have a complete handle on this, but it is the work that we will be doing in 1994 and thereafter. We know it from our work with the lymph nodes, the thymus, and from the stroma of the bone marrow. It is conceivable that, even if you destroy or block all the virus in a person, or even if you try to re-infuse cells, you will not be able adequately to reconstitute the immune system unless you provide a proper microenvironment in which those cells can thrive. That is why we are starting to think in terms of the kinds of therapy, either with cytokines, or even replacing tissue, like thymus implants, that re-establish the lymphoid system microenvironment.

You ask what did the bone marrow transplant studies tell us? They told us, since they were unsuccessful, that we are probably dealing with two things: one is a virus that is still replicating. We know from our lymph node work that there is plenty of virus in the body and it is replicating, even though it appears from looking at the blood that there is not much virus around. That was one of the most important results to come out of our recent studies on the lymph nodes. But also, in addition, it tells us that there is destruction of the milieu that the immune system needs to regenerate and re-establish itself.

Although the data were generally negative, that is, the bone marrow transplantation did not work, I think this work provided extraordinary insight for future experiments that we are conducting now and that I think we will probably be conducting for the next five years.

Harden: Let me follow up on this point. I was fascinated by your recent Dyer Lecture that seemed to take all the findings from the beginning and pull them together into a picture of the pathogenesis of AIDS. As we have been looking through a number of documents, we have come across the names of people in your laboratory whose work contributed to this picture. I thought perhaps you could tell us how your laboratory functioned and which groups were working on which pieces of the problem.

Fauci: Certainly.

Harden: Let me list a few names: [Dr.] Scott Koenig, [Dr.] Steven Schnittman, [Dr.] Guido Poli, and [Dr.] Tom [Thomas] Folks. Perhaps you could describe how these people interacted.

Fauci: We had a number of individuals, who were predominantly fellows, who were in their training period. I assigned different tasks to each of them, to work in a particular area. I tried to cover, as best as I could, the salient areas that I felt would be important from an immunopathogenic standpoint, because the underlying theme of the laboratory was the immunopathogenic mechanisms of HIV infection.

We had the original work that I have mentioned with Cliff Lane looking at hyperactivity of the immune system and at some of the selective T-cell defects. But then Cliff made a major switch in commitment to doing clinical investigations and clinical trials. He still maintained his interest in basic science, but he has provided an invaluable component to the laboratory now by translating what we do in the laboratory into clinical trials, both immunological reconstitution as well as the antiretroviral work.

At that time Tom Folks was in the laboratory. He had been working formerly as a fellow with [Dr.] Ken [Kenneth] Sell, and when Ken left, he joined me in my laboratory. Tom and I had a very productive interaction in the laboratory where we were involved in establishing permanent HIV-infected cell lines and beginning the work on looking at the role of cytokines in HIV infection.

Tom left and went to the CDC [Centers for Disease Control and Prevention], but in the few years that Tom was with me we collaborated well. There was also an Italian named [Dr.] Guido Poli, who had come from Milan as a postdoctoral fellow. He worked with Tom and me for a year or two. Then, when Tom left, Guido blossomed as the main player in the cytokine work. He has been very productive in delineating the role of TNF [tumor necrosis factor], GM-CSF [granulocyte-macrophage colony-stimulating factor], IL-6 [interleukin 6], IL-1 [interleukin-1], interferon gamma, interferon alpha, and other cytokines in the regulation of HIV expression. In addition, he studied the autocrine and paracrine loop of cytokine regulation of HIV. He continues to do that to this day. He has been with us now for several years and unfortunately, he will be leaving us to return to Italy soon.

In addition, we had [Dr.] Scott Koenig, who, again as a fellow was interested more in how the body responds to HIV. He did very important work, I think, in delineating the role of cytolytic T cells in clearing HIV. He stayed at NIH for a few years, made some important contributions, and then moved on to MedImmune Corporation.

At the time that Scott was here–I try to stagger my fellows by bringing in new people as others get more senior and leave–a young man from Italy named [Dr.] Giuseppe [Gepi] Pantaleo came into the laboratory. Gepi Pantaleo has been one of the most impressive researchers in the laboratory. He started off as a young fellow and now is making major contributions. At first his area was looking at the cytolytic cells, taking over from Scott Koenig, but then we got very interested in the role of viral burden and replication in the lymph nodes. He is now focused predominantly on that, and he and [Dr.] Cecilia Graziosi are working together on it in the laboratory. So the laboratory has the Guido Poli mini-group that is interested predominantly in the cytokines. It has the mini-group of Gepi Pantaleo and Cecilia Graziosi working on the viral burden in lymph nodes and on viral replication.

Then we had another smaller group that was interested in precursor cells. That was work that was started when [Dr.] Steven Schnittman was a fellow in the laboratory. Steve demonstrated, for the first time that thymocytes, in vitro, even the thymocytes that were not expressing CD4 molecules grossly but were so called “triple negative” cells, were infectable by HIV. He published a very important paper on that, and he also did some of the viral burden work in the peripheral blood. Steve did this work in my laboratory at the time he was getting ready to leave and go to the extramural program. [Dr.] Sharilyn Stanley took over this work when Steve left. Now she is leading that mini-group looking at the effect of HIV on the thymus, the thymic microenvironment, and the bone marrow, and looking at the effect on precursor cells. Hers is another mini-group that is also doing very important work in that regard.

Then we brought in [Dr.] Andy [Andrew] Dayton, who is working with a group on looking at control of viral gene expression, particularly the rev axis; so we have a molecular virological approach there.

We also have people who are much more senior and independent who are not predominantly working on AIDS, but who do HIV-related work. [Dr.] Uli Siedenlist, who has been very much involved in cloning and describing the role of the NF-kappa-B transcription activating factor, is fundamentally a molecular biologist. He is now using that expertise to look at how HIV uses the NF-kappa-B access for virus expression and how cytokines use the NF-kappa-B access to induce HIV. Finally, [Dr.] John Kehl is another former fellow of mine who is now a senior independent scientist. He has trained [Dr.] Peter Ruckmann, a fellow from Germany, to perform some very interesting work on the role of B-cell derived cytokines in the induction of HIV expression.

All of these lines of research are now, I think, synergizing in the laboratory. When a critical mass is created, then all of sudden you can look at the big picture, at everything. You have the cytokine look, the precursor look, the viral burden and lymph node look, the molecular virology look, and the clinical immunological reconstitution look. All of those things create an atmosphere in the laboratory that is perfectly suited for producing the results you heard at the Dyer lecture. I was able to get up and talk about the whole spectrum of HIV pathogenesis. People feed and nourish each other. It is good when there is a critical mass of people all interested in the same general theme, HIV, and how it destroys the body's immune system, with each person investigating it from a slightly different perspective.

Harden: You are in the position of doing basic research, of being very intimately linked to work on AIDS, and, at the same time, you are in the public spotlight as a chief spokesperson for AIDS. Beginning with Peter Duesberg, and most recently in Robert Root Bernstein's book Rethinking AIDS, the question has been raised, “Maybe HIV is not the cause of AIDS?" Perhaps you would comment on the value of rethinking AIDS. How many times do we rethink it?

Fauci: I do not think it is a question of totally rethinking AIDS. I think it is a question of keeping an open mind about the mechanisms whereby the virus destroys the body's immune system. There is no question that the primary component of AIDS is the virus. Since there were not complete, precise explanations available of how the virus destroys the body's immune system, some people made an inappropriate leap. They said each and every pathogenic event could not be explained on the basis of the virus killing a cell, because it was perceived that there was not enough virus around or there were other phenomena going on. Then, in a sense, they threw the baby out with the bath water. They said that the virus had nothing to do with it. It was just behavior. People were taking drugs, and people were leading “promiscuous” sexual lives. Behavior itself was causing AIDS.

The epidemiology, in and of itself, completely destroys that argument. But rather than take a very strict unidimensional view, what we do–in my laboratory–is realize that we do not have the complete explanation of how the body's immune system is destroyed. We work on that. We know that without the virus, there is no disease. But if you have the virus, how do you get the disease? Rather than arguing about whether the virus is involved or not, we say, “There is no question the virus is involved; but, how is it damaging the immune system?” That is what I tried to get across in my Dyer lecture in the spring of 1993, and in my plenary lecture in Berlin at the International AIDS Conference. I spoke about the multifactorial, multiphasic components of the immunopathogenesis and viral pathogenesis of AIDS and how that would give us insight into the design of therapeutic strategies.

We can now look at a prototypical HIV-infected individual and the different phases of HIV disease. It is not the small window that we saw in 1981, where a person would come in who was drastically ill, and the only thing that we saw was someone who had no T4 cells and was very sick. But if someone is watched from the beginning to the end of their illness, we see that there are multifactorial components of HIV disease. There is the virus itself, there is activation of the immune system. There are other indirect mechanisms like inappropriate cell triggering, probably apoptosis to a certain degree, cytokine secretion, regulation of HIV expression, a disrupted microenvironment, and the profound immunosuppressed state. These are all complex issues that need to be dissected out. We must keep an open mind because everything cannot be explained by a single unidimensional approach. Without the virus, nothing happens; however, the virus of itself does not explain everything directly. That is the critical issue. That is how I handle it when people say, “No, it is not the virus. Just throw it out.”

It is interesting because there are many diseases whose pathogenesis we do not understand, but nobody questions what causes those diseases. For example, we do not have a very good idea of why people who have tuberculosis get granuloma. Why does caseation occur? Why do we get cavitation? People will say, wait a minute, sometimes if you look at the caseating lesion in someone with tuberculosis you may not see very many microbes. Does that mean that the tubercle bacillus is not responsible for the pathology? No, the mechanisms are the induction of a variety of inflammatory and necrotic processes. Just because each and every pathogenic event in AIDS cannot be precisely explained is not a reason to say that HIV is not the primary mover in AIDS.

Harden: Thank you. When you began your research, you did not know what you were dealing with. How did you approach the biohazard problem? Were you worried about your own safety, and your colleagues' safety?

Fauci: No. From the beginning we took the approach that we would be as careful as we possibly could without being hysterical about it. There was really no substantial fear. Maybe there should have been, but there was not. Certainly there was no fear in taking care of patients. We had been trained from the time we were in medical school that it is our responsibility to take care of sick people. If someone does not want the responsibility then he or she should go do something else. There was never a question in my mind, or in Cliff Lane's mind, or in the minds of the people who came after us, that this was what we had to do. We decided we wanted to do it.

continued on Page 03


Previous Page | Next Page (2 of 6) Office of NIH History | NIH| DHHS