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Harden: One of the things in which we are very interested is your thought process as you approached a totally new disease problem and worked it out.
Blattner: Well, it was not easy and it was not clear. An example of one wrong turn on our part was our first AIDS paper published in the Lancet in 1982. Unfortunately as a by-product of this paper, we were labeled as the group that thought that amyl nitrite caused AIDS. In retrospect, it is easy to see how our analysis was confounded. People who had the most severe immune deficiency had the strongest history of amyl nitrite use. What this really reflected was the fact that people who had the heaviest nitrite use were the people who had the largest amount of anal receptive sex. As a result they probably got the virus earliest.
The other thing that was somewhat astonishing about these data was the insight they provided into the gay life style. Many of these men had a large number of partners. People had sixty to a hundred partners in a year with the bath-house sex and all the other things that were going on. Many investigators were people who were not involved in STD [Sexually Transmitted Disease] research and certainly not very aware of the gay life style. This was all a little overwhelming in some respects. A positive aspect of this study was to show the extent of CD4 damage in non-AIDS high-risk persons. This was one of the first publications to show the extent of CD4 abnormalities in gay men at risk for AIDS.
Harden: Was there opposition among the scientists to looking into this disease because it was a disease of the gay population?
Blattner: I did not sense that. I wrote a review of Randy Shilt's book And the Band Played On for Scientific American. It gives some insights into my thinking. Basically, the NIH has a system that is excellent for promoting research, but this was not research as usual. It took a while to appreciate the extent of the AIDS problem. There just have not been any other pandemics recently. There was a lot of sentiment in the early eighties that pandemics were not possible in this day and age. The NIH has an approach that works for solving problems, but it may take several years to get money into the pipeline in the extramural program. I think one of the advantages and the strengths of the intramural research environment is that you really do not have to justify your research in advance. You are given money and an ounce of faith to go out and do good research, and in five years an outside site visit team comes back to tell you if you still have a job. The scientist must make choices, but it does create an opportunity to take somewhat higher risks than people are able to do who have to apply for grant money.
I have not gone through the grants process, so I do not know, but it is my understanding that key people on the study sections make the decisions as to what research gets supported. These people also tend to be fairly conservative in the review process. There were a lot of applications at the time of the early epidemic coming from researchers like Friedman-Kien and some of his people, for example. These applications were getting shot down in the study sections because people did not appreciate the nature of AIDS. It is hard to put forward hypotheses and have the study section deal with them. There was one episode in 1982, when the first money for the MACS [Multi-Center AIDS Cohort Studies] was released. This actually was a significant NCI initiative that was not appreciated. We had dry runs in which we tried to justify why we were requesting money. I was not directly involved in that, because it is an extramural activity, but I can remember advocating that the first million dollars should go towards AIDS epidemiology research. In the extramural program, it is more of a process. The grants getting process was not prepared to deal with the realities of a new pandemic that was totally unexpected and totally undefined at the beginning. There has never been a disease like AIDS. I hope to God there is not another one. At this time, AIDS was really the proverbial elephant–everybody had his or her hands on the elephant but could understand only a portion of its components.
Rodrigues: What were some of the events or findings that turned your thinking away from the lifestyle theories, like the amyl nitrite theory, as causes of AIDS? Was it the epidemiological findings that finally pushed those other theories off to the side or were there other laboratory findings?
Blattner: The work of the CDC and the expanding number of persons like hemophiliacs identified as at risk for this syndrome were two things. Our own studies of the epidemiology of CD4 cells, which showed that levels were associated with certain sexual transmission behaviors, also influenced our thoughts. Some alternative theories remained until the day of the press conference in which Gallo got dragged out on stage by Secretary [Margaret] Heckler for the announcement that the AIDS virus had been discovered. You can go back and look at publications talking about all the theories. Some of the early issues of AIDS Research, for example, summarize some of these theories. There were charts showing too much semen and too much blood–suggesting immune overload and collapse. Here was a virus that kicks in EBV [Epstein Barr Virus], so on and so forth. There were some publications on the work that Jim Goedert did looking at the cohorts. He started to get things right in terms of using T-cell subsets as an exposure marker, to use epidemiologic parlance. There was evidence that people who had lower T-cell subsets were infected. In fact, that was one of the conclusions, but these papers got overlooked because other papers came along. We were analyzing the subset data.
It was in late 1983 that we were beginning to formulate a pattern of transmission of the disease. One of the key aspects of this is that when you do data analysis, much time is spent on cleaning-up of data and file organization, so that you can actually manipulate the data and get the parameters condensed into something that is meaningful. There is a lot of leg work that can take months. All this was going on, when in early 1984, one Sunday morning, we were invited to breakfast with Bob Gallo at the Bethesda Marriott. He told us that he had the cause of AIDS in a continuous cell line. We were able to move quickly and get samples that had been retained from the cohort studies. There were many people who had ideas on how to use our serum. There was a famous CDC case control study. By the time the cause of AIDS was discovered, as far as I know, all the sera from that case control study had been used to look at just about everything. Bob Biggar and Jim Goedert stuck to their guns and held it in reserve until a likely cause was found. There was a lot of pressure to look at HTLV-1 as one of the possible causes.
We had links with Bob Gallo's laboratory and a direct computer link to the BioTech laboratory where some of the first plates for the ELISA were developed. The technology that had been hard won between 1981 and 1984 for HTLV was used quickly in the HIV issue. Even with the fairly imprecise test, we were able to prove epidemiologically that HTLV-III was etiologically the cause of AIDS. These papers came out in the fall of 1984, within a few months of Gallo's papers. They are hardly ever cited; people often cite the next wave of papers that show the same thing, but those came out at least a year later.
Harden: You were involved with the rebuttal to [Dr.] Peter Duesburg's assertions that HIV does not cause AIDS. Your paper in Science arguing for HIV as the etiological agent was based on epidemiologic criteria, but your response to his arguments was based more on laboratory findings–fulfilling Koch's postulates. What you have been describing to us is a confluence of laboratory research and epidemiological studies. Could you explain further what evidence convinced you that the retrovirus HIV was the cause of AIDS?
Blattner: Going back to 1984, it was a gut level intuition that led to this insight at the time of the publication of the Gallo papers. The situation at that time was one where we had spent several years thinking very intensely about the problem and gaining insight through epidemiological study of CD4 subsets in high risk groups. This was not a time when we got much sleep. We worked on these problems and went up a lot of blind alleys. All of a sudden, in the summer of 1984, we ran a test, the one discovered and reported by Gallo for HTLV-III, and everything fell into place. What we were dealing with was suddenly crystal clear. We did not need a lot of semantics to know that we were home. In some respects, it is like pushing a button, and all of a sudden a door opens. You start to understand things.
Harden: You are convinced that it is not a fluke.
Blattner: Yes. One hundred or 99 percent of all the signs that we had anticipated should be associated with AIDS and its etiological agent were right. People who had intact T-cell subsets were not antibody positive; people who had severely depressed T-cell subsets had antibodies. People who had a lifestyle that put them at greatest risk for infection were infected; people who engaged in safe sex and did not abuse drugs were not as likely to be infected. Of people for whom we had serological samples, those who sero-converted developed AIDS. People who did not seroconvert did not develop AIDS. These findings did not answer every question that Peter Duesberg has raised. But, at that time, after the frustration of fighting this problem, this was a big step.
We had done some experiments–Dean Mann, Jim and Bob, in our laboratory, where we reproduced AIDS in the test tube by monitoring CD4 counts. We never published this research because we were never able to isolate the virus, but we reproduced the disease in the test tube. When we co-cultured umbilical cord blood, the T-4 cells disappeared, so we knew that there was something going on in the test tube that was killing T-4 cells. It may have been one of the first demonstrations of this phenomenon; I do not know. There are a lot of firsts, but many people make these discoveries.
Harden: Why do you think that Duesberg persists in his criticism?
Blattner: I think that he must be very sincere in his belief. I think that it has to do with the fact that the AIDS virus is so different from any other virus that we have seen. We are used to viruses causing diseases in a short period of time. The HTLV virus has taught me otherwise. Duesberg does not believe that HTLV causes ATL either. It has to do with how you think as a scientist. He is a very brilliant guy and an excellent scientist, but we think differently. When I see something like the HTLV virus that can be transmitted from a mother to her offspring, and then some thirty or forty years later, show up as a leukemia, I see a great opportunity to understand the fundamental biology of cancer. It gives us a hook on what is going on in the process of cancer. I cannot satisfy Duesberg's criteria that HTLV causes ATL. I believe it to be so. I am not going to live long enough to be able to prove it because of the long latency period. But I can try to understand it from the biology that is emerging from the study of this virus. HTLV seems to have the ability to select clones of cells that multiply. Those cells burn out, and then these little mini-tumors disappear. I think that is a pretty good analogy to a lot of cancer. There are many smokers walking around who have had spontaneous cures of their lung cancer. Who knows why? We do not know. I look at these as opportunities to expand our horizons.
I guess that Duesberg is legitimately concerned that we might be barking up the wrong tree because this virus behaves so differently. The major concern, just like our misinterpreted paper about amyl nitrite, is that there are so many opportunities for coincidental agents being present in the AIDS setting. That was the whole problem. There was a man from NIAID who held a press conference only weeks before Gallo's one claiming that a fungus caused AIDS, because it created a substance analogous to the immunosuppressive material used in kidney transplants. You are probably aware that there were a lot of opportunities to discover all kinds of opportunistic agents in AIDS. You come to something like HIV and then you are really stuck. Is HIV a pathogen, or is it a passenger? I think Duesberg is on the fence on that issue. I personally think that the evidence is overwhelming that HIV is the cause. We will see in a paper to be published this month from Mitch [Dr. Mitchell] Gail, a statistician, that treatment is impacting the AIDS epidemic and that AZT [3'-Azido-2', 3'-dideoxythymidine] probably has changed the course of the epidemic, at least among gay men.
So, in time, all of Peter's concerns will to be answered. Transfusion intervention will be recognized as preventing AIDS. Treatment targeted at the virus will be shown to be of benefit. Ultimately Peter has made the mistake of confusing cause with understanding pathogenesis. We know the cause of AIDS is HIV. However, we do not know how it brings about the actual AIDS illness. This is an important issue that will take time to solve. Many pathogenic organisms are known to cause disease, but the way they cause disease is not yet known.
Harden: Historically, it has happened both ways, of course. A new agent that does not fit the paradigm is eventually shown to be the cause in one disease scenario. In contrast, there have been many, many times when people have erroneously declared an agent to be the cause of a disease.
Blattner: That is absolutely true. If we did not have Peter Duesberg, it would be bad, because we need people to raise these kinds of questions. There is a potential for harm when there is a lack of attention to detail, which I felt in Peter's response to us on the transfusion issue. He did not acknowledge, or study well enough, the complexity of the statistics that were being examined to be able to dismiss them. But the real potential for harm in that situation is that it may reinforce the denial of people that AIDS is a sexually-transmissible disease, allowing people to place themselves in unfortunate circumstances where they may become infected. Denial is a very strong human emotion. It is very strong in any serious illness or disease. Here we have a situation in which we cannot afford denial, because to deny is potentially to give someone a death sentence. To avoid therapy for something treatable because there is a lingering doubt about its cause is also not good. That is where I see the danger.
Rodrigues: There was serious concern about the risk of infection for health care workers in epidemiological work, and you were involved in reviewing the needle-stick injuries. Could you comment on that?
Blattner: I think that early on we were not as smart as we could have been in our own precautions. Thank God, nobody in our laboratory got the infection through that route. But early on, I do not remember us wearing gloves very often. If you had a blood spill, you would wipe it up. Not being concerned about things like that was stupid. Gallo's laboratory was overcrowded, and his staff was overworked. There was a lot of tension; fortunately, nobody got infected. As we began to gain insight from the work with our cohorts of gay men, we expanded our activities. We had actually started our surveillance of laboratory workers in the HTLV era, because it was an infectious agent. They actually became a study cohort.
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