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In Their Own Words: NIH Researchers Recall the Early Years of AIDS
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Interview with Dr. H. Clifford Lane

This is an interview with Dr. H. Clifford Lane of the National Institutes of Allergy and Infectious Diseases (NIAID), at the Clinical Center, Building 10, of the National Institutes of Health (NIH), in Bethesda, Maryland. The interviewers are Dr. Victoria Harden, Director of the NIH Historical Office, and Dennis Rodrigues, Program Analyst. The interview was held on March 12, 1990.

Rodrigues: I'd like to begin by asking about your professional training and your background before you came to NIH. How did that lead you to become involved with patients with PCP [Pneumocyctis carinii pneumonia] and Kaposi's sarcoma?

Lane: I did my training in internal medicine at the University of Michigan. Afterwards, I came to NIH in 1979 to do a clinical associateship–a fellowship training in infectious diseases and immunology. My initial research was studying the normal adult human immune response.

Harden: Let me back you up for a minute. Who offered you the fellowship?

Lane: I came here to the Laboratory of Clinical Investigations as part of the NIH Fellowship Training Program. So Mike [Dr. Michael] Frank would have been the person who made the offer. That program allows you to do clinical training and also spend time in the laboratory. I spent time in the Clinical Physiology Section of the Laboratory of Clinical Investigation. That was Tony [Dr. Anthony] Fauci's section of that laboratory. He was a section head at that time. So, that was how I came here.

My initial work was studying antigen-specific human B-cell responses. I was studying how normal volunteers respond to immunization, and through that, trying to understand how the adult immune system worked. You may or may not be aware that a lot of the work in immunology involves pediatrics, or developing immune systems. There isn't as much work, or at least in the past hadn't been as much work, studying the adult human immune system. Immunology research often focused on either pediatrics, because of the immunodeficiency diseases of kids, or on the immune systems of small animals. In any event, I was doing this sort of work then.

Harden: This was in 1979, when things were peaking after the early explosion in immunological knowledge, was it not?

Lane: Hybridomas were just being made. It was before the molecular biology innovations had really become established, so it [immunology] was still predominantly a cellular science. It was just before, I would say, things really took off in immunology.

Harden: What did you hope to do at that time? Where did you see your career going at that point?

Lane: I was interested in studying the way the immune system recognized specific antigens and decided to make antibody to A rather than to B, C, D, E, and F. I was interested in how that process was regulated, with an eye on trying to better understand autoimmune diseases. In fact, I began to collect a cohort of patients with a disease called Sjogren's syndrome, which is a disease of oligoclonal B-cell activation. Basically, I was studying specific responsiveness and hyper-responsiveness of the immune system.

Around 1982 or 1983, when I'd just been extended to stay on beyond the usual time, which is three years, there were a couple of different patients on our ward. Steve [Dr. Stephen] Straus brought one in. I don't know when [Dr.] Henry [Masur] came here exactly, but Henry had brought in a couple of patients as well. The patient Steve brought in just had immunodeficiency. I don't know if that patient had AIDS or not. But it was just an unusual immunodeficiency disease. Steve studies herpes virus infections, and the patient had severe herpes virus infections. To this day, I don't know if anyone knows if that patient was HIV-[human immunodeficiency virus]positive. In any event, shortly thereafter, when AIDS was something that people were aware of, Steve brought in a couple of patients with AIDS. Henry and Tony [Dr. Anthony Fauci] were starting to bring in some patients with AIDS, and I was in the laboratory, helping one of our technicians, who was also doing some basic research with me, some immunologic profiling of these patients as they were coming in. She was looking at a variety of immunologic functions in these patients. I wasn't really involved in that directly other than by giving her a little bit of advice. I had other projects that I was much more interested in.

Then two things happened to me at about the same time. I was looking at some of her data with her. At this time, we knew there was a T-cell defect and that there was a numerical decrease in the helper cells–that had been published. But what struck me from the information she was generating–no one had really looked at this–was the amazing polyclonal B-cell activation. The B-cells of these patients were just incredibly turned on, more so than in lupus patients. This was something that I had been studying in normal volunteers. I had been looking at some autoimmune diseases, but this B-cell hyper-reactivity was something that superseded any of it; so I got very interested. I then started studying the mechanisms of the polyclonal B-cell activation in patients with HIV infection. That got me going on the laboratory side of things.

Harden: Did that then lead you into the study of how the B cells were also affected?

Lane: Yes. Actually, we had a paper published in the New England Journal of Medicine around 1984, which was sort of the outgrowth of that work. Working on it took about two years; we did a lot of things to put everything together. But an interesting thing happened to me at about the same time that I started becoming identified as someone in the laboratory with an interest in the immune systems of these patients. I started taking a little bit more active role in looking at patients with Lynn Edgar–looking over Lynn's shoulder–and we started working on it a little bit more.

Then one day I remember I was down in the intensive care unit in Building 10, talking to [Dr.] Henry Masur. Henry said that he had just seen a patient in the clinic with AIDS, and the patient had an identical twin brother. Would I be interested in doing any immunologic studies on that patient? The thing that jumped to my mind was what a great opportunity to do some in vivo immunologic studies. We could do bone marrow transplantation between this guy and his twin brother without a need to ablate the patient.

There had been some attempts at bone marrow transplantation, but when you condition the recipients with cytotoxic chemotherapy and radiation, they die. This had been the experience up to this point with everyone using ablative therapy. So I was interested. This was around 1982 or 1983, I don't remember exactly. I said, “Well, yes. Why don't we bring this person in and talk to his brother and see what we can do.”

So I talked to the patient and his brother and they were interested in pursuing something like this. I can remember vividly that we admitted the patient in July; probably 1983, I'm not sure. And the first thing we did was get together a group of people–Tony [Dr. Anthony Fauci], myself, [Dr.] Henry [Masur], [Dr.] Dan Longo from the [National] Cancer Institute, and someone from the [NIH] Blood Bank, [Dr.] Harvey Klein, because we decided eventually on a program where we would do adoptive transfer of lymphocytes. We would take lymphocytes from the healthy twin, give them to the patient with AIDS, and then, after doing that study, see what happened. Then we would do a bone marrow transplantation. So we brought the patient in in July; we gave him the first few doses of lymphocytes; followed what happened; and then did the bone marrow transplantation that fall, I think in September. We watched with great excitement, because we saw the T4 count come up in the patient after we infused the lymphocytes; then it went right back down. Then, after we did the bone marrow transplant, the T4 count came up and it stayed up for a while. We were getting extremely excited. This was before HIV, before we knew what we were really dealing with. We were monitoring skin tests. The skin test response was getting bigger, and the T4 count was going up. So we were ecstatic. But then the T4 count started going down. The patient developed Kaposi's sarcoma, after which he developed cytomegalovirus [CMV] retinitis. The interesting thing was that up to this point, I had not been involved clinically. But right now I run the [NIAID] intramural clinical program, and this is how it happened. With this patient, I spent hours every day in his room explaining what we had done that day, what the lymphocytes were doing. Because I gave him the skin test myself, I wanted to be sure it was given the same way. I would give him the skin test, read the skin test, talk about something new, whatever. I would just spend hours and hours. Then, it was horrible–he started to develop CMV retinitis. That is a progressive, destructive disease of the retina where you go blind.

We tried high-dose acyclovir first, but that didn't do anything. That got me thinking, “Well, what else can we do?” What could we do? We had some work we had done in the laboratory. We had looked at some of the defects in cytotoxic cell function. You could boost cytotoxicity with interleukin-2. But interleukin-2 wasn't ready to go into clinical trials yet. We had tried hard. Humans had not received interleukin-2 at that point in time. So there was another T-cell derived lymphokine, gamma interferon. Gamma interferon had been, in clinical trials, a natural product, not a recombinant product. A doctor in the Cancer Institute named Steve [Dr. Stephen] Sherwin, who went on shortly thereafter and became a vice president at Genentech, helped me in this. Steve helped me get some gamma interferon to treat this one patient. From there we developed a gamma interferon study in a larger number of patients. But the problem was that gamma interferon did nothing. In fact, if anything, it hurt these patients. In that particular clinical trial, that agent was not helpful. This is now six months or so later, and the patient's CMV retinitis is getting worse, and he is now starting to go blind. We had worked very hard to get the interleukin-2 contract in place.

We went through procurement. You know what a nightmare that is, and it cost us, I forget exactly, about $250,000 to get interleukin-2, just enough to do a reasonable clinical trial, not on just the one patient but on several patients. We did finally get all the approvals. This is about the same time that Steve [Dr. Steven] Rosenberg was starting to use interleukin-2 in some of the cancer patients. It was the exact same thing, because we were talking to Steve at that time about the best route to take, all the different products, and the pros and cons. So this same patient who had gotten the bone marrow was the first to get gamma interferon, and then the first to get interleukin-2, in any clinical trials. He went blind from CMV retinitis with interleukin-2. We had a little bit of excitement because it has some immunomodulatory effects. But by itself, it doesn't do much either. That patient eventually died here, but in the interim, he became the impetus for looking at immunomodulators–lymphokines, cytokines–in patients with HIV infection. That work continues up through today. So, we went into interleukin-2 trials. Now we're just getting into 1984 with the discovery of the virus. From there the emphasis clearly shifted to looking at agents that could block replication of HIV. So, that's really the early story, or at least how I got involved in the things that I was doing.

Harden: Your reason for being drawn into this was very clinical. It was due to these patients that you were involved in trying to find something to stop the disease process as opposed to research on any possible causative agent. Do you remember the various kinds of theories that were around?

Lane: Oh, sure. My interest was in what was going on with their B cells, so I had a research interest that was separate from looking for a cause. Most people at that time suspected that this was a retrovirus because of what was happening to T4 cells. We knew about HTLV-I [human T-cell leukemia virus I], and we were providing samples to anyone who had ways to try and find an etiologic agent. Samples were going over to the Laboratory of Tumor Cell Biology in Fort Detrick [Maryland]. In fact, they had some isolates at Fort Detrick shortly after [Dr. Robert] Gallo's paper in Science came out. So that actually was an independent confirmation of a retroviral-like agent from samples from these patients. We were helping to support that type of work, but we were not doing that type of work ourselves. What we were doing was trying to characterize immune defects.

So while all the clinical work was going on over here, we were looking at the B cells and describing their activation. Since it was a T-cell disease, for the most part, we were trying to focus on the nature of the immune defect. We were then able to home in very precisely, in a descriptive way, and say that the defect was an antigen-recognition, antigen-induced activation. This fit in nicely with what I had been looking at earlier, which was the role of KLH [Keyhole-limpet hemocyanin] and a specific antigen with the adult's human immune response. If we could immunize the patients with KLH, they would make no antibodies, and therefore they would have no T-cell responses.

It was mind-boggling looking at how immunodeficient these patients were, because I'd been seeing normal volunteers for three years, and I knew what someone should do when exposed to this very potent immunogen. We would immunize the AIDS patients, and they would have no reaction. It was very fascinating because it was the first time that people were looking at that. You just don't expect it. Now, it's “Oh sure, of course.” But when it was happening, you were saying, “Wait a minute, I immunized this guy with five milliliters of KLH; he should have 18,000 units of antibodies.” But there was nothing. Their T-cells don't respond. At that time, we didn't have flow cytometry the way we do now. We were doing laborious physical techniques, like separating the helper cells from the suppressor cells. We were studying them separately because people thought there was too much suppression with the imbalance in the helper-suppressor ratio. We worked on that and looked at these cells. Clearly that wasn't the case. You could tell. The suppressor cells were there, in fact, they should have functioned normally, but they couldn't without normal inductive signals. It was the lack of that inductive signal from the helper cell that was the defect. So, that was work that we did. That was another New England Journal of Medicine paper that came out. I think it came out in 1986.

continued on page 02

 

 
 
 
       
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