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Harden: The tremendous interest in AIDS extends to virtually every field. When we held our 1989 conference on the history of AIDS, we had an experience similar to yours. We scheduled a conference room that would hold fifty people. Many people called me saying, “I just have to come to this conference.” A scientist/historian from Italy said, “I must come and tell you what we're doing.” We never dreamed that the history of AIDS would have generated as much interest.
You noted that Dr. Sever was the person who named the disease Simian AIDS. When did he do that?
Gay: It was just before the 1983 meeting, but it may not have been much more than twelve hours before. When he wanted to call the etiological agent SIV, I accused him of wanting to call it “Sever's immunodeficiency virus.” It was just before the meeting.
Harden: Did he choose the name “Simian AIDS” because it would be good publicity or because it was more descriptive?
Gay: Very descriptive.
Harden: You have noted that animals at the California center provided evidence that the agent was transmissible. What was the evidence, and how early did the researchers see SAIDS as an infectious disease?
Gay: It was by 1982. It was well before the virus was isolated. I cannot tell you whether it was December 1980 or December 1981, but it was well before. The animals were kept in large outdoor corrals, which were about 50 by 100 feet, fenced with cyclone fencing. As the scientists divided the animals, they took strips of land and built the corrals side by side; a middle fence divided them. That was all you needed because the point of the fence was to keep the animals from fighting. The scientists at the California center knew that SAIDS was transmissible because the disease would spread in one partitioned area, then it would show up in the next one and, then it would spread further. That was about as much evidence as they needed.
Harden: Was there any evidence that it was sexually transmitted?
Harden: Was there any evidence that it was transmitted through biting and scratching? Was blood-blood contact necessary to transmit it?
Gay: I do not know whether they knew that blood-blood contact would spread it, and I do not know how soon they started trying to transmit it by hypodermic needle.
Harden: Essentially, then, by early 1983 they knew that SAIDS was transmissible, but they were not sure of all its parameters and the epidemiology?
Gay: That is correct.
Harden: I raise this because it seems to me that much of the 1983 meeting–the second session especially–was concerned with epidemiology and biosafety. Were there concerns about humans being infected with this agent? Or were the concerns primarily about the spread of the disease among the animals?
Gay: The concern was primarily the spread among the animals. In dealing with infectious diseases of primates, you always worry, because they are so closely related to humans, whether you are going to be the first human to contract the disease. Because of this, you tend to do autopsies in a cap and a mask and a gown and double gloves.
Harden: Primates bite and scratch too, don't they? You must have to deal with that as well?
Gay: You bet. Yes.
Harden: That meant that there were many opportunities for humans to get infected, if the disease was infectious for humans.
Gay: I do not think there was any more concern about that then. There was general concern about monkeys and the agents that they carry. They have a very nasty herpes virus that, in the last three years, has killed two veterinarians. They have an oral herpes virus called Sabin's B virus. They have tuberculosis often. The chimpanzees have hepatitis. I spent the latter part of my first year at the NIH in the Clinical Center suffering from a chimpanzee hepatitis. We all face these things. I do not remember any special concern about that with the Simian AIDS. Everybody continued to be as careful as they always were.
Harden: Looking at some of the comments in the JAMA [ Journal of the American Medical Association ] coverage of the 1983 meeting, it is apparent that things were not yet clear. Dr. Gallo had not yet announced his discovery of the virus, and even Montagnier's article came out the month after the meeting. People were leaning at that point towards a virus as an agent, but nothing was settled. Dr. Wolff noted that no sexual differences in the primate victims of SAIDS were observed, yet people were still looking at AIDS as a male homosexual disease. Were the people who worked with primates saying, “This is a virus that could affect everybody,” from the evidence that in primates there were no sexual differences in terms of who got it? Was anybody willing to generalize to humans from those data?
Gay: I do not remember whether they did or not. I do not remember anybody pointing out that if animal caretakers were exposed to SAIDS, the human female was likely to be spared.
Harden: Dr. Gene Shearer of NCI [National Cancer Institute], noted that the AIDS-like syndrome in juvenile macaques would be useful in studying AIDS in children, but not in adults. Can you tell me why? Is the immunology that much different?
Gay: No. But, in the macaques with SIV there is a neurological syndrome, especially in the younger macaques, which is very similar to the one in people. I do not think they knew that much about it at that time.
Harden: Much later, in 1986, it was known that SIV infected the brain, and you described it then as an exciting feature. Why were people excited about that fact?
Gay: Because HIV did not make chimpanzees sick, and there was not any model for the neurological involvement in AIDS other than SIV in the macaques.
Harden: There was a great transition period in the history of AIDS after the second DRR conference in March 1984. Dr. Gallo's papers and announcement in April 1984 that a virus was the cause of AIDS were accepted at that time as solving the etiological problem. In November 1984, another meeting on animal models for AIDS was held at the Rocky Mountain Laboratories. Did Gallo's announcement change anybody's point of view on what was going to be discussed about the kinds of animal models you were looking for?
Gay: Yes. To some extent. This November conference was organized by [Dr.] Lois Salzman, who was in the Allergy Institute at that time. She chose NIAID's Rocky Mountain Laboratories in Hamilton, Montana, because we were not able to contain the size of the meetings here in Bethesda, and Hamilton is not very accessible. Only the really devout AIDS enthusiasts showed up in Hamilton, Montana.
Harden: Do you have any particular comments about the November 1984 meeting?
Gay: My main comment on the RML meeting is that participants made a real attempt to look at other retroviruses and other animal models. The retrovirus of the cat is not unreasonable. If we did not have monkeys, we would be probably be doing more with one of those retroviruses, such as feline leukemia, for which a vaccine has been developed. I can remember [Dr. Richard] Dick Krause announcing at a scientific directors' meeting that there was no vaccine against any retrovirus. It was most unusual for Dick not to know about the cat vaccine.
The feline leukemia vaccine does not work very well. This retrovirus vaccine is a hazard because you have to test the cat for the retrovirus before you give the vaccine. If you give the vaccine to a cat that has the retrovirus, it breaks down the immune system. The cat generally gets sick, and most of them die. In 1986 or 1987 the California Veterinary College, in collaboration with the Primate Center people, discovered the FIV [Feline Immunodeficiency Virus]. It came from a cat in San Francisco and is more closely related to SIV and HIV than to feline leukemia. Huebner had worked with a mouse retrovirus. There was a real interest in looking at other viruses by people who were "bench" scientists. They were not the Max Essexes and the Bob Gallos and the Murray Gardners getting together. These were people who were injecting the animals, growing viruses, and so on. That was another characteristic of this meeting that made it different. It was calculated to be that way, and it was. Dr. Salzman's book is an excellent review of the meeting.
Harden: Many scientists have used mice in their studies. Were the scientists concerned with the cost of primate models, or did they use mice for certain specific things and then come back to primates for other studies? How do you determine which model is going to be the best?
Gay: People who are determined to study AIDS but who cannot afford the primates will probably turn to the mouse retrovirus. I do not know the mouse retrovirus system very well, but it is not nearly as similar to human AIDS as is SIV in the primates, in terms of the infected white cells having some similarities. Probably the mouse is not a bad place to screen, but you can do a fair amount of screening in tissue cultures of the white cells infected with the virus. I do not think the mouse is a major model for AIDS, except in the SCID [Severe Combined Immunodeficiency Disease] mouse. Are you familiar with that?
Gay: Do you remember the Houston bubble baby? The SCID mouse is a bubble baby mouse. It essentially has no immune system. You can sew human skin on the mouse's skin and it will survive; the skin will grow. Furthermore, if you inject human white cells into a SCID mouse, the white cells will set up housekeeping and reproduce. Now you have a mouse that has a human immune system which you can infect with AIDS.
Harden: You noted that budget expansions for AIDS were incredibly rapid. The amounts doubled between 1983 and 1984. They doubled again in 1985. AIDS research began to overshadow other research projects in the primate centers. Could you elaborate on that a little?
Gay: I do not think so. That pretty well covers it.
Harden: Did the centers drop research in progress? Were they able to hire more people to keep some projects going? What does “overshadow” mean in this context?
Gay: It means that AIDS research received all the new space and all the new money, as well as all the attention and publicity. I do not know of any major projects that were discontinued, however. Much ophthalmology research was going on at the New England center and at Atlanta. None of that was dropped. A lot of work on other infectious diseases was being done at Delta, Tulane, and California. None of that was dropped. Reproductive biology was a major focus at the Oregon center. I do not think any of that was dropped. There may have been a few infectious diseases projects that fell by the way as people turned their attention to AIDS, but I do not think that any other major projects were dropped.
One of the two things that are very important at the primate centers is neuroscience research. Working with an animal with an extremely well developed nervous system and reproduction system is important simply because they are very similar to humans. I do not think that any projects in the neurosciences or in reproduction were dropped. Probably none of the behavioral science projects were dropped, either, because behaviorists do not have much of a role in infectious disease work. In fact, there are some behaviorists who do not believe in the infectious disease theory. At least, that is the belief of some of us who have to work with them. You cannot seem to convince them that you cannot put all the animals together and keep them well. Overall, I do not believe that many projects were dropped because of AIDS.
Harden: Did the new money and the status associated with AIDS cause any problems between people?
Gay: Yes. But I do not remember any crises because of it. Dr. Leo Whitehair could probably answer that in greater detail.
Harden: In the summary of the 1986 Napa Valley meeting, Dr. Gardner was very enthusiastic about certain models for AIDS. However, in Dr. [Jorge] Ribas's document, dated 27 October 1986–it was the background for the December 1986 conference sponsored by Walter Reed Army Medical Center–he said in bold type that there were no satisfactory in vivo models for AIDS. What was he talking about? Why would he say that?
Gay: I do not know.
Harden: Did a whole group of people think that there were no good models?
Gay: There is a group of people who are very disappointed because there is not an animal into which you can put HIV and get AIDS. Ribas is part of that group.
Harden: What was the connection of the groups working with the Army on AIDS? What was the Army's interest other than protecting its own personnel?
Gay: To avoid getting credit for spreading AIDS overseas.
Harden: So you are saying that they were looking for an animal model that could be infected with HIV rather than exploiting the SIV model?
Gay: The Army always wants a quick answer.
Harden: Did the primate centers work well with the Army? I believe they accepted a number of contracts from the Army.
Gay: As the person who administered the program, I feel that, yes, we did work well together. We received a large contract from the Army that Dr. Dennis Johnsen managed. The centers and the Army worked very well together. I found Ribas a good man to work with. Do you know Colonel [Donald] Burke? Colonel Burke is the [Dr.] Anthony Fauci of the Army. He is in a class with Tony, too. He is very good. Burke and [Dr. Robert] Redfield–who is a very good scientist but who is also a little cynical; he occasionally makes colleagues angry–are always looking for an answer. Burke is spearheading a vaccine trial in Thailand now. He is very well informed. He and two other researchers have certain advantages because they can examine their population in the army closely. When troops come in, they can examine the population annually, and they can check whenever anyone goes through the hospital. As a result Burke has the best epidemiological records on AIDS in the world, except those of the former Soviet Union.
I once asked him about the incidence of AIDS in Africa. When he told me, I asked where his data came from, since he did not do the tests himself. He replied, “I exchange information with the Soviets, and they test everybody who comes in.” He really was busy globally. Burke is a great contributor in this field; anybody who was thinking of having a meeting on AIDS should include him. I have always found the military nice to work with. That is not the case with many of my colleagues. But I had a good time in the Defense Department and I have had a good time with the Defense Department researchers since I left.
Harden: Is it better doing research on animals since you can exert control over variables like diet that you may not be able to regulate in humans? Do you get your results faster that way?
Gay: I think the results of studies with animals are more reliable. The rate at which results are obtained depends on the animal being studied because animals generally have a shorter life span than humans, except possibly the chimpanzee. Due to this shorter life span of the animal, some pathogenic agents have a shorter incubation period. This means you can get enough data for a paper in less than five years, which is fairly quick.
Harden: When I interviewed [Dr. Kenneth] Ken Sell at Emory in 1988, he commented that everybody was concerned over the new finding that SIV isolated from a sooty mangabey suddenly seemed to have mutated to a highly virulent form.
Gay: I remember that very well.
Harden: Could you elaborate on what happened and what the outcome of that incident was?
Gay: The outcome was that the agent became a standard for testing in the macaques. You got quicker results that way. That episode bothers me because retroviruses modify all the time, and HIV could mutate into a highly pathogenic form. HIV-2 from West Africa is not so pathogenic. Viruses that are not so pathogenic are going to die off. I do not know what is going to happen when we get a more pathogenic one. We have seen it happen in the cat–that FIV cat from California. We have seen it in the primate virus–the one from Emory. Stay tuned for it to happen with HIV.
Harden: If I remember correctly, if a virus mutates to a form that kills its host rapidly, the only way it can continue to survive and reproduce is by finding a quicker route of transmission. If HIV mutated to a virulent form that was transmissible through the air by sneezing, we would be in bad shape.
Gay: Yes. I do not know of any retrovirus that has airborne transmission. But, yes, we would be in bad shape. That happened with the Pasteurella organism. I am reading a book on the effect of infectious diseases on history. The author talks about plague, which began with the bubonic form. When a pneumonic form appeared that was transmitted by sneezing, it moved a lot faster.
Harden: Could you bring us up to date on what has been happening in animal research on AIDS during the last three years, since about 1989, and what you see as the important lines of research now?
Gay: I really have not been going to the meetings and keeping up, so I do not think you should take my comments as authoritative. I have been following very closely developments with the pigtail macaque, which have been very interesting. In terms of host susceptibility, one has to ask whether the people in Seattle are working with the same virus that we were working with in 1985, because that virus changes all the time. Maybe Dr. Ribas will finally have his model. Another very interesting development is the SCID mouse model that I mentioned. I think that is going to provide an excellent means for screening potential AIDS drugs, but I do not know whether that is going to be better than [Dr. Thomas] Tom Kindt's rabbits–he's still struggling with those–or than [Dr. Malcolm] Martin's mice. You can do marvelous things with transgenic animals, and the researchers may get one yet that is more susceptible. We also have plenty of chimpanzees now, though I notice that writers like Gina Kolata, who writes for the New York Times, say that there are not enough chimpanzees. There are plenty of chimpanzees for vaccine trials now.
Harden: Do you think that any of the candidate vaccines being developed look promising, or is the mutation of the virus so fast that none of them will be able to provide protection?
Gay: I think that producing immunity against these retroviruses will require an entire system of immunization. It will not be like immunization against flu or polio–three shots and you are immune. It will take a bigger boost than that. [Dr. Harry] Meyers, who used to be in the Bureau of Biologics and now is at Los Alamos, has been tracing the enormous differences in the HIV viruses that he has isolated from around the world. Nobody says this, but as a less than well trained immunologist, my interpretation is that the whole thing may be a kind of a lottery: if you take the vaccine, you will be immune to some strains but not to others. That is why I think it will take some system of immunizing beyond just one or two shots. It will be a real struggle to get a vaccine that will protect against all kinds of AIDS.
Harden: Would you make an overall assessment of the contribution of primate models and other animal models to research on AIDS?
Gay: My assessment is that most of the really good basic research has depended on animal models. This has been a more animal model-dependent disease than most that we have experienced, because we do not have any human patients who have survived. We are even more controlled on what can be done with patients than we used to be, but we have dozens of agents all the time that we need to screen. DdI [2'-3'-dideoxyinosine], AZT [3'-Azido-2',3'-dideoxythymidine], the antibiotics, all of those things have been screened against animal retroviruses before they have gone to the clinics. Another point to note is that there has been an evolution in animal models since AIDS was identified in 1980. With transgenic technology, which we are not able to apply to rats yet but which is being applied to some other animals–sheep, cattle, and mice–we can create types of susceptibility that were not possible before. We have the SCID mouse, in which we can do screening that we could not do before. Thus there has been a real evolution of animal models, which may help.
Harden: Do you think the public understands the importance of animal models?
Harden: What should be done to change that?
Gay: Something should be done to change the public's view on the use of animals in all types of biomedical research. Look at the work [Dr. Thomas] Tom Starzl has done on organ transplantation. Starzl was a grantee of NIAID in the late 1960s. All of the work done by immunologists has also accrued to help the AIDS campaign. But all of this research has been extremely important for successful organ transplantation, even the techniques needed by surgeons in order to do it. I was glad to see [Dr. Joseph] Murray at Harvard finally get the Nobel Prize for his kidney transplant work. [I was very interested that he gave a lot of credit to a chap from England, named Dr. Roy Yorke Calne. He is now chairman of surgery at Cambridge. Murray wrote a chapter for me in volume II of my book, Methods of Animal Experimentation. He gave a lot of credit to Calne for bringing the basic immunology from [Dr. Peter] Medawar's laboratory to Murray's laboratory.] Medawar was a great immunology animal experimenter. I think it is interesting. But the public really is not much interested in this sort of thing.
Harden: Just the final results.
Gay: No, they are not interested in research in animals, but the importance of research animals is clear and it does make a big difference. I think it is unfortunate that we find animal rights material being presented to schoolchildren now, because that is going to create a problem. If you had occasion to practice veterinary medicine you would understand. I had a real dose of this in New York City. “You say my dog has worms? Well, what's that?” “Do you know what an angleworm is?” They did not know what an angleworm was. They had never seen a worm. Increasingly as we recruit people to work in the laboratory animal field, we find that we have much more training to do, because now our student population comes to us biologically illiterate. That causes a problem in understanding the environment, and the crisis we now face. I have talked with people working in AIDS education. You have to teach people biology before they understand where AIDS is coming from and what it will do to them. I guess, biology is not interesting to many people, and I do not know how to make it glamorous. I am not a good educator, but it must be done if we want to help people.
Harden: Thank you very much, Dr. Gay.
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