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Harden: That was the first AIDS patient.
Yarchoan: That was at least the first that I had seen.
Harden: We know about this patient.
Harden: But go ahead.
Yarchoan: After this patient came, we became aware that the CDC [Centers for Disease Control and Prevention] had become aware of several cases similar to this, especially in New York City and Los Angeles. So we figured out that, whatever this disease was, this patient seemed to fit the mold. In retrospect, he was a textbook case of AIDS. As I recall, Tom Waldmann tried doing some studies of him, and basically the patient just did not have any peripheral blood T-cell lymphocytes to study. Then the patient wound up getting one opportunistic infection after another. I think he may have gotten Pneumocystis pneumonia. He was a young, previously healthy man, and we had no idea what the disease was. There were heroic efforts to keep him alive and treat him, and nothing really worked. I think that several months after he came to the NIH, he finally expired.
Harden: But were you intimately involved in his care, or were you one of the group? We have had several people describe coming in to see this patient.
Yarchoan: I was one of the fellows that covered on that ward, but I was not the person primarily responsible for him. But we cross-covered on him and we often discussed what to do about him. So I was one of the people involved in that sense.
Harden: But this was probably too early for panic to have set in among the staff. Were there any special precautions that you remember?
Yarchoan: No. This was just another immunodeficiency patient who came in.
Hannaway: But you did regard this person as extraordinary.
Yarchoan: It was pretty wild, seeing someone who had been healthy and who then came down with such profound cellular immunodeficiency. We were all struck by it. I remember that one of the clinical associates, [Dr.] John Missiti, got very interested in him. John went up to Baltimore to try to learn what recreational drugs were being used in the gay community there. He tried testing the drugs in the laboratory to see if one of them was causing the T-cell deficiency. One of the theories being considered was that some drug being used by this population could be causing this T-cell deficiency.
Harden: Do you remember when the idea that it might be caused by some sort of a virus or an infectious agent first came up? Was it early on or was it after you got more patients that you could see a pattern?
Yarchoan: What was apparent early on was that this was occurring in the gay population. An infectious agent was always a possibility, but I think the first real evidence was when a report came out–I am going to say a few months later, but it was probably six months or so–that the disease appeared to be spread by blood transfusion. That was the real indication that it could be spread by some sort of transmissible agent. There was a lot of concern at that time about this.
I also remember that my wife, [Dr. Giovanna Tosato], had heard from her mentor, [Dr. Michael] Mike Blaese, that there seemed to be some children in Newark with a new immunodeficiency. She had gotten some blood from these patients through Mike and she had been trying to study the immune function of the cells. In retrospect, this was pediatric AIDS, but we didn't know it at the time because the disease had not been described. No one used any gloves working with these patients, and there were no other special precautions taken at that time, because we didn’t think of the disease as infectious.
Harden: We will come back to that question, too. In this early period, were you interacting with people like Dr. Robert Gallo as the move towards understanding the cause began? My recollection is that it was late June 1982 when the hemophiliac cases and the transfusion cases came to light. So it was later that year that Dr. Gallo started working on this problem. Were you at all involved in his work?
Yarchoan: I really was not. I did a lot of thinking about it. But I had my own project going on at the time. There was also a sense early on that it was tough to study this as an immunologic disease because the immune system was so wiped out in the patients who had what we now call AIDS that it was hard to isolate T cells from the peripheral blood.
Harden: So you did not think of yourself as an AIDS researcher or get involved until the point you were talking about earlier, when Dr. Broder was going to set up an AIDS therapy unit around 1983 or 1984, after the virus was discovered?
Yarchoan: Setting up a unit makes it sound like a bigger deal than it was at that time. I think he had just been appointed as head of the Clinical Oncology Program, but he still had only a single module. Then he moved up to the thirteenth floor in the Clinical Center, probably sometime in late 1982 or early 1983, and I joined him around January of 1984.
Harden: To do AIDS work?
Yarchoan: To do work on retroviruses and AIDS. The problem that he faced was that without a causal agent to work with, it was hard to develop rational AIDS therapy. There was a lot of interest in Sam’s laboratory at the time looking at HTLV-1. Remember, the first human retrovirus, HTLV-1, had been discovered just a few years earlier in Gallo's lab, and soon after that the second human retrovirus was discovered by him. This was a very exciting period. And HTLV-1 seemed to be a way of studying immunodeficiency caused by an infectious agent that you could get your hands on. There was good evidence that people with HTLV-1 infection did have some sort of immunodeficiency. Also, other animal retroviruses caused immunodeficiency. So we spent part of our time trying to study how HTLV-1 caused immunodeficieny, thinking that this might provide some sort of model for what was going on with HIV.
Harden: I have two more questions along this same line. First, did you have any sense of urgency or frustration with the people, the activist community, the press, saying, “We have to have a treatment?” Did you have any sense that you should be trying to find something?
Yarchoan: No, I do not think so. I was pretty isolated from such outside criticism.
Harden: At that time. Okay.
Yarchoan: I remember at the time that there was more of a sense that we needed to first understand what on earth this thing was before we could effectively work on treatment.
Harden: My other question comes back to what you said a minute ago about it just being fantastic that you had these human retroviruses. It has been pointed out by other people that it was almost mystical that the first human retrovirus was identified in 1979 and 1980, and then we have this epidemic caused by one in 1981. Do you have any comments on that?
Yarchoan: Yes. It was a very exciting time. On one hand, the discovery of the retroviruses opened up a number of avenues of research. But AIDS showed us that something that no one ever worried about before suddenly could become a major problem for the country and for mankind. It was as though there was a whole new area that opened up, and at the same time had to be opened up, in order to address a new public health problem.
Harden: But perhaps you knew enough about animal retroviruses so that it was not a totally foreign concept.
Yarchoan: Correct. Remember, Bob Gallo’s group had been looking for human retroviruses for years and years.
Harden: Of course. But they had not actually been able to demonstrate one.
Yarchoan: They had not been able to demonstrate one, and then suddenly you had several retroviruses to study.
Hannaway: This next question is a more general question to lead into the question of treatment. I wonder if you would comment on NCI’s drug discovery program as it existed about the time that AIDS appeared. Was this seen as a valuable program by NCI’s administrators and scientists? What was the status of the drug discovery program?
Yarchoan: Which drug discovery program are you particularly describing?
Hannaway: The one that Dr. Broder had been involved with.
Yarchoan: I first need to clarify something. During much of that time, I dealt with Sam and Sam dealt with the rest of NCI. I did not deal directly with Vince DeVita very much. The impression I got was that Sam was given some resources to start an effort, and he was given additional support when he asked for it for a specific step in the research. Sam often described our group as a SWAT team, by which he meant a small, very focused group of people, rather than a large, bureaucratic program. I never figured out whether the SWAT team existed because it was the way Sam wanted to work or because the institution provided relatively few resources at that time. But the impression I have is that things were moving very quickly, that there was not a set program. It takes time to get a program in place. A lot of the effort at that time was made by individual scientists who were interested and who felt that there was a public health crisis that they wanted to help address. Sam would be the best one to speak with about the specifics. I did not get a sense that there was overwhelming institutional support for what he was doing initially.
Hannaway: He expressed the view to us that he felt that the National Cancer Institute and others were naïve about the process of drug discovery. How do you find out if drugs work in particular instances?
Harden: And yet the National Cancer Institute had a historic commitment to drug discovery. It was the only institute that did.
Yarchoan: Yes, but it was focused on cancer drug discovery. Actually, cancer drug discovery and antiviral drug discovery are very similar, but they are also, in many ways, very different. You could find out a lot more about anti-infective and antiviral drugs before they went into humans than you could about cancer drugs, at least at that time. In that era, cancer drug discovery was relatively primitive. If something seemed to selectively kill certain cancer cells more than it did normal cells, that was often a rationale to consider further testing as a cancer drug. But with a virus, you can get a substantially better sense of how selective the agent is before you put it into people if you have a good in vitro testing process. So initially there were just a few people testing therapies, but there were no large, established efforts to develop therapies or drugs for AIDS.
Hannaway: What were your views about the possibility of treating retroviruses. Some scientists thought that they were not going to be treatable. Can you remember how you thought at the outset? Did you think that you were liable to have any success in searching for treatments?
Yarchoan: The easy answer is that I did not have a clue. But it seemed worth trying. It seemed a possibility if there was a virus causing AIDS. We did a certain amount of brainstorming. My best recollection of the events is that [Dr. Luc] Montagnier’s paper, which described a virus he was calling LAV at the time, came out around November of 1983. I may be off by a month or two. In the same issue of Science was a paper–I think [Dr. Edward] Ed Gelmann was one of the co-authors with Bob Gallo–in which they were describing the possibility of HTLV-1, or a variant of it, causing AIDS. Even though Montagnier turned out to be correct, it was hard to get a sense of whether LAV was the cause of AIDS from that initial paper, and there continued to be ideas put forward about possible causative agents. There was even an article several months after that suggesting that some type of cyclosporin A analog caused by a fungus might be causing AIDS. So, in the period of time from November of 1983 until about May of 1984, we continued to focus on HTLV-1, because it was not clear what was causing AIDS, and at least we had a good model to study.
Then the series of four papers came out from Bob Gallo's group. Sam had heard first from Bob Gallo that he had something exciting; then we got the embargoed copies of the galleys of those papers and were able to read them just before they came out. When you read those four papers one after the other, you really felt it was nailed down that this was the cause of AIDS. And that information caused us to redirect our efforts towards therapy. Sam sat us down and said, “Look, there is a small possibility that the idea is wrong, but let us put our marbles on this one. Let us really think of what we could do.” Sam was quite taken with the idea that you could treat this disease and that this would be our focus.
We discussed this a lot. We thought that this was a virus that infects CD4 cells. It was probably killing CD4 cells directly after infecting them. It seemed fairly straightforward. So this suggested that ongoing viral replication was continuing to be an issue in patients with AIDS and continuing to cause the destruction of the CD4 cells.
We knew that the immune system had some ability to reconstitute itself, and that by blocking this process, there was a good chance that the immune system would come back at least partially. So there was at least value in blocking viral replication with an anti-HIV approach.
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