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Harden: That brings another question in my mind. How fast was research moving here at NIH as compared to the other places?
Lane: Well, this is awful to say, I guess, but I think that we were light years ahead. I think we were moving extremely quickly.
Harden: Is that because they needed to apply for grants to get money and so couldn't get moving, whereas you could?
Lane: I think so. I don't know. I don't think that the people weren't qualified. I think they were qualified. That's the strength of NIH. It's a horrible thing for a taxpayer, but if tomorrow I wanted to do something different, I would do something different. When I got reviewed by the Board of Scientific Counselors, they might have recommended that I get the boot. But nonetheless, I have that sort of independence, that freedom where I feel I can do that; I can do something new. You can move quickly into something new, as long as you have the support, like we did from Ken [Dr. Kenneth] Sell. That helped us moved very quickly. We really did. The funny thing is that we moved quickly, but it's not as if we got space all of a sudden, or we got people all of a sudden. Those were very tight constraints. FTEs [fulltime equivalents] were like gold; they still are, but not for AIDS. We've had it pretty easy going for the last several years, and we've been able to build because of that. We've gotten money, space and FTEs in the last few years. But in the early days, we didn't have any of that. We just had our own initiative to move into new areas, and that was supported. That was good. NIH moved extremely quickly, and despite all the bad things that people write about what went on here, I think we moved very, very quickly. I think we made a contribution because of that, which I don't think any other place could have made. We had patients here, we were seeing the patients; we were trying to find [etiological] agents, trying to understand the immune system, and a lot of good work got done. But, you know I'm totally slanted.
Rodrigues: Given the criticism that was coming from different quarters, how did that affect you and some of your other associates? Was it troubling to hear people on the outside saying things such as: NIH didn't know what it was doing; the effort was completely disorganized; or there was no leadership?
Lane: It was a matter of looking at where those comments were coming from. That never bothered me, I have to say, because I never felt that way. I never felt that was going on, and I didn't feel if an objective person came in and looked at it, that they would feel that way either. Yes, there was a need for so much, but one place could only do so much. One disease has so much priority in the public health of the nation. When I looked at it and tried to put it into perspective, I thought we were doing a good job from that point of view. The people who were very critical were often from the lobbying groups, the gay community. I can understand them wanting more, more, more. They were saying what I would have said were I in their place. You have to be on one side or the other if you want to make change. They wanted to make change, and I understood what they were saying. It didn't make me feel persecuted. We were seeing a lot of gay patients. I knew very little about the gay community; I became very good friends with the local gay community over time because of what we were doing. I found them very supportive of what we were doing. The criticism to me wasn't directed at NIH or the scientific community. It was directed at the government, the Congress. That was how I felt it. I didn't feel it personally as someone at NIH.
Harden: This is what I feel. I think sometimes the blame is displaced onto the wrong agency of the government. I've been attacked on occasion because I was representing NIH. The political process sometimes is what people were unhappy with, the leadership at the top. Not to mention frustration because their friends are dying. People observed this same phenomenon with the Three Mile Island incident; the CDC apparently couldn't even get in and do studies because the people wouldn't talk to them because they were the government and these people were so unhappy with government.
Rodrigues: Leading up to some of the work that you're doing now–given the availability of therapeutics–probably with AZT [3'-Azido-2',3'dideoxythymidine] and ddI [2',3'-dideoxyinosine], if you repeated the same bone marrow transplant experiment how do you think it would turn out?
Lane: Well, we've done that. I can answer that precisely; it would not have turned out differently. We still don't get rid of the virus. The virus is still there. You can get transient improvement in immune reconstitution, although with time it still falls off. You're probably aware of the one experience at [John] Hopkins [University] where they claim eradication of HIV. I don't know; only time will tell if that's accurate or not. I tend to be skeptical of it; because I don't think you can eliminate every infected cell–just some cells. The monocyte/macrophage reservoir is going to be resistant to those types of ablative therapies. The risk to that patient was great. That patient died shortly after the conditioning regimen, 44 days, or whatever it was. In any event, we have repeated that work; and in fact, that work goes on.
I'll tell you what we're going to do next. We looked at AZT plus bone marrow transplantation plus lymphocytes in syngeneic twins. Actually, we have a paper in review on that right now. We did sixteen [such transplants], because we thought we had some good results with bone marrow transplantation alone, and we knew that there were good results with AZT alone, so we put the two together and thought we might be able to get something more substantial. We really couldn't. What we're going to be doing next is looking at a combination treatment regimen of AZT plus interferon plus [soluble] CD4 to try and block the virus. What we're going to do now is see how it all fits together. That's one of the nice things about it. We're also doing a Phase I vaccine trial with gp160, a full-length envelope protein. We now have good dose-ranging data on that toxicity, so we know how to immunize someone to gp160. We don't know if that protects them from HIV, but we know how to immunize someone to gp160. We're going to immunize the [bone marrow] donors to gp160, so the immune system we transplant, the lymphocytes we transfer, will be primed to gp160. We'll have an immune system that we're transplanting that's already primed to at least some of the antigens of HIV. So, those are some of the things that we're doing differently. But that is where that work is at present. Plus, there is one other thing we're thinking of doing again with Mike [Dr. Michael] Blaese and [Dr.] Steven Rosenberg in the Cancer Institute. They have techniques for growing enormous numbers of cells, these TIL cells–tumor infiltrating lymphocytes. We've talked about getting some gp160 cell lines or clones from our immunized donors who have the identical twins. We will grow these clones, or those cell lines, and then infuse those into the HIV-infected people. The foundations for many of the things we are doing now were back in those days when we didn't know what we were dealing with. We were looking at it as an immunologic disease and trying to come up with strategies.
Harden: This then moves into my next, two-part question. I was reading Bill [Dr. William] Paul's presidential address to the Society of Immunologists, and one of the things he was saying was that, at that time, immunology lacked a quantitative approach. It was pretty qualitative but not quantitative. What kind of impact has AIDS made on improving immunological knowledge, in general, and quantitative knowledge, in particular?
Lane: That's a very good question. I think it will, but it hasn't yet. I'll take one thing that AIDS has done for immunology. It has justified all the FACS [fluoroscent-activated cell sorters] that were ever made, and all the monoclonal antibodies that were produced. The T4 [CD4 cell] count of value is an example where the clinical immunologist can really play a major role in helping management of the patient. When the count goes below 200, that patient is at risk for Pneumocystis carinii pneumonia. If that count is above 300, that patient probably isn't going to get Pneumocystis carinii pneumonia. So that is a very quantitative assessment of immunologic function based on the number of circulating CD4 cells. I don't think that is what Bill is referring to in his presidential address, but at least it is a quantitative assessment. What I think we will learn from the study of patients with AIDS and HIV infection is the precise role of the CD4 cell and its subsets in regulation. The way we'll do that is as we find out, as the memory clones are selectively infected. But others are infected as well. If we take the elements that are infected away, and then try and replace in some more precise fashion different elements of a specific immune response and try to rebuild what was destroyed, I think we can. It will help if we get some quantitative information about which cytokines are important. So basically we have an experiment of nature where there is a selective injury at least early on, and I think the more selective the injury is, the easier it is to find it. We will be able to do that with time. We haven't done that yet; we've described it, but we haven't really understood it. So I think we're still at that point.
Rodrigues: Another question I have has to do with the CD4 receptor. What normally hooks on to the CD4 receptor?
Lane: A class II MHC [major histocompatibility complex] molecule; it's felt to facilitate or stabilize cell-cell interaction. So, if you have a cell that's presenting antigen to a T lymphocyte–let's take a monocyte or macrophage–that cell will engulf, let's say, a foreign protein. It will digest it into fragments, and some of those fragments will bind inside the cell to the class II MHC molecule. Then antigen and class II MHC will be presented on the surface of the monocyte or macrophage. CD4 cells recognize antigen in association with class II MHC. The T-cell receptor will bind to the MHC-antigen expressed complex, and then the CD4 receptor will bind to class II to stabilize that cell interaction. Now CD8 plays a similar role for the CD8 cell in class I MHC, so in the induction of a CD8 response, we generally have a protein made within the cell, like a virally infected cell making viral proteins. Those viral proteins will associate with class I MHC and be expressed in the surface of the cell; the CD8 antigen receptor will recognize antigen in the context of class I MHC, and then CD8 will bind to MHC class I to stabilize that cell-cell interaction. It doesn't appear to be in the place of CD4-class II MHC complex; it doesn't appear to be an essential binding to get cell activation. Blocking that interaction is what happens in AIDS–the cell is infected and destroyed. You can block that interaction with soluble CD4, for example, and you still get antigen presentation and antigen activation. Well, does that answer the question?
Rodrigues: Yes it did. Is there much variation if you look at a CD4 receptor? Is there variation in the molecular structure of that protein?
Lane: There is. In fact, there's a very common variant of CD4 receptor seen in the black population, and I can remember an interesting experience with this. This has been recognized for about four or five years. We were studying a patient with HIV infection–he was a black patient with KS and with no CD4 cells, and I, of course, said, “Well, this patient, immunologically, looks very bad. I think he is at high risk for infection.” Four years later, the patient is doing well. What it turned out to be, I don't know, maybe it was the case with this patient. In the interim we learned about the Leu-3A antibody. Leu-3A is the CD4-HIV gp120 binding epitope. That epitope, one of the classic and first antibodies used, was made by Ortho. Leu-3A antibody used in CD4 cell tests recognizes an epitope on the CD4 receptor that a certain percentage, maybe 5 or 10 percent, of the black population don't express. So there is some heterogeneity there. I don't know anyone who has had heterogeneity in the HIV binding site, which is in the fourth domain. I've never heard of a naturally occurring mutation in CD4 receptor that prevented the binding of HIV, but that certainly could be possible. To answer your question, yes, there is some heterogeneity within that molecule.
Rodrigues: Have you had any interaction with or involvement in the international arena? This seems to be one component of this whole story, that hasn't been covered as well as we think.
Lane: Well, you're going to get a story now. I guess that's what you're after. This was either in 1983 or 1984. Dick [Dr. Richard] Krause could probably tell you exactly. The decision was made from the NIAID director's office–Dr. Krause's office at that time–that it would be important for NIAID to send a group of people to Haiti, because we had this disease. It was before HIV–it must have been 1982. It must have been 1983, I guess. I don't know. In any event, he wanted to send one person with clinical experience, another person who knew immunology, and a third person who knew epidemiology to accompany him to Haiti. I got a call and was asked if I would be interested in accompanying the director on the trip. I was just out of my fellowship at that time, totally awe-inspired, but to be honest, I really had no desire to go to a country that might be the seat of AIDS. I enjoyed studying in my own controlled laboratory, and I didn't want to go to some hotel where I wouldn't know how the water would be. So, I said, “No thanks. I'd really rather not go.” And they said, “Well, we'd really like you to go.” I said, “Really? I'd rather not go.” I heard this second-hand, but I believe it's true, knowing him. When he got the second refusal, he said to someone–Ken [Dr. Kenneth] Sell, probably–“Is Dr. Lane a member of the Commissioned Corps of the Public Health Service?” Dr. Sell said, “Well, yes, he is.” He [Dr. Krause] said, “Well, then, I'm ordering him to go.” So, I thought, “Oh, what the heck. I'll go and I might as well make the best of it.” So, I packed up my suitcase with water and candy bars and headed out with them. We went down to Port-au-Prince, and it was a very enjoyable visit. I had to come back and give a lecture. In fact, I ended up there a day by myself. We met with the ambassador and the minister. It was one of these official type visits that I don't really find a lot of fun. We got into the hospital a bit and actually saw a patient–a woman with very severe genital herpes. So, when I came back after giving the lecture, we brought some intravenous acyclovir down. I then saw when they were ready to put the IV [intravenous line] in, they had this jar of straight needles. I mean, not butterflies–just straight needles that they reused. It was just so enlightening to me–my having only seen medical care in the United States–to see the bedpan, buckets, and flies. This was a University Hospital–an open-air hospital. They had private clinics that were quite a bit better. Seeing them, and talking with people down there, made an interesting story for me.
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