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In Their Own Words: NIH Researchers Recall the Early Years of AIDS
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On the positive side, many of the things that are currently available have given reasonable immune response in animal models. The animal models are virtually impossible to predict one from another. The way to go forward is in human testing. Enhancing antibodies have not been demonstrated in the work with the protein in the Phase I trials that have already gone on. The data is not outstanding in any one, but there is enough evidence that sometimes you get protection in animals to be tempted to go forward.

I guess, if I had to weigh in on one side or the other, I would like to see the testing of the vaccine, because I am 58 years old and I want to see some results and know what is going on.

No. To be serious, I think I would lean towards having some trials go forward. But no one is in a position to predict the outcome. We talked previously about [Dr. Ronald] Desrosier's argument for the use of live virus vaccine. I said that I did not like this argument and I said that to Desrosier early on. You have probably seen that subsequently to that [Dr.] Ruth Ruprecht at Harvard has shown that with that approach baby monkeys got AIDS. I did not think a few years was long enough for Desrosier to wait with the other, nor did I think he could predict from SIV to HIV. Nor did I think he could predict ten years down the line of the population at large all developing a cancer of some kind. Yet I know the argument. The argument is, if your back is against the wall and you are in some special place and there are so many infections, what can you do? It is one of those real “catch-22s,” but I think the dangers far outweigh the argument to go forward. I believe approaches through vectors like the adenovirus or the canary pox virus, or the NYVAC from Virogenetics that we are collaborating on, have given enough at least reasonably interesting data to go forward with vaccine trials in humans to get some baseline data. But I cannot predict that there will be a successful vaccine next year, or two, five, or ten years from now, or ever. I think there will be one.

Harden: You think there will be eventually?

Gallo: I think there will be. I would not take Albert Sabin's approach, that there cannot be a vaccine, because we cannot imagine the science that is developing. There are all kinds of new things happening. I am attracted by some ideas that [Dr. Myron] Essex has been promoting recently in the model systems that he has talked about with cat leukemia. There are brand new types of experimental approaches. My former coworker here, [Dr.] Jonathan Gershoni, who is now back in Israel, has some interesting approaches that no one has tried before. I think there is so much going on right now...But the downside of all of this is that the companies are getting out of vaccine research, and obviously the companies are needed. Whereas in research we often hear from the lay public how cooperation is needed and competition is bad, usually the opposite is true, sometimes we have almost too much cooperation. Competition is good–it stimulates fields–but in this case, for an AIDS vaccine, there is no question that we need total cooperation. We need, I think, government's involvement, or some kind of world leadership, an agreement where everybody comes together and perhaps gives a certain percentage of their GNP [gross national product] towards the research. I am not certain, but I think the companies fear lawsuits. They do not have incentives, the research is expensive, there is no assurance of success, and so they have real difficulties in deciding to stay in vaccine research. Most are not, as far as I can tell.

There are people out there trying to promote research. I know that in Connecticut and in New York there is a group trying to raise a very large amount of money by multiple different mechanisms predominantly for a preventive vaccine. The Sabin Foundation, in fact, with Eloise, Albert's wife, is involved in this and I think it is headed by a man named H. R. Shepherd from Connecticut. He has talked to me several times and I think it is a very exciting endeavor. I hope he succeeds, because, if they get the kind of money they want–they are trying to raise half a billion dollars or more, $600 million dollars–they should fund three or four centers, rather than giving out grants to support basic research or clinical research by thousands of investigators everywhere. They should gamble on three or four centers and say, “Here take $25 million dollars, take $50 million dollars, take it for five years–you do not have to publish–just come back once a year and give a report and, at the end of the five years, we hope you have something" and maybe force them to work with one of the major industries. Something like that is going to be needed to develop a vaccine unless we are very lucky.

Harden: The other approach to dealing with AIDS, besides vaccines, is, of course, therapies.

Gallo: Yes.

Harden: Perhaps you would comment on the hydroxyurea therapy, the prospects for gene therapy, and give an overview of other forms of therapy that you think might become available?

Gallo: Let us maybe back up. As you know, we probably have touched on the fact, to some degree, that the standard approach to HIV therapy right now is the targeting of enzymes of the virus. Those are what can be screened. That is what companies can get into most easily. That is where the most information is available. Reverse transcriptase, protease, and, ultimately, probably the integrase. Some of these proteins have been crystallized, their structures are known, and molecules can be designed to fit those structures. Companies can screen because they can do an enzyme assay. Also, you can just screen large numbers of compounds.

Part of that work has led, early on, to the nucleoside analog approach, to AZT, ddI, and ddC. All these are reverse transcriptase inhibitors. The problem with this approach is the escape mutations. It looks like these therapies will never be highly effective.

We were all hopeful that the protease inhibitors would do a lot, and they have; they can greatly reduce virus. However, it looks as though there is escape pretty rapidly from those protease inhibitors. That is disappointing. In my mind it is extremely disappointing. I think that sets people back. I would not give up on the protease inhibitors. I think they are a powerful class of antiviral compounds. But it does mean it is probable that we need to invent other approaches.

There are a large number of other approaches and a large number of investigators involved. With therapy there is more commercial incentive. There is less likelihood of lawsuits and less likelihood of doing damage, because the person is not normal. With a preventive vaccine, you are involved with normal, healthy people. With therapy there is also something to sell. A company does not go broke. It is not only for the Third World because, speaking in reality, much of the urgency for the preventive vaccine is in the Third World, as you know. So there are incentives here. This is not the problem. As I said, you could talk all day about the myriad approaches to therapy being taken by academic investigators and by the pharmaceutical industry, but the predominant industrial approach still remains targeting the enzymes and the problem still remains of escape mutations in patients and sometimes, though not always, toxicity.

To speak specifically about my laboratory, we are focusing on about four different approaches. One is what might be called a molecular approach. That is, the antisense [RNA], which is a collaboration with a company in Massachusetts called Hybridon, that Paul Zamichnek got me started in many years ago, I think in 1986. We have been working with that company on and off since then. We have a smaller, similar collaboration with Lynx in San Diego, on the antisense approach.

Now an antisense can be given subcutaneously. Hybridon is trying to develop a form to be given orally. But it can also be delivered with a liposome, perhaps, or, by the means you asked about, gene therapy. You can use antisense in gene therapy too. What do we mean by gene therapy? Yes, we are involved in it, and yes, I think it is one of the few theoretical chances for a home run for AIDS, but it has its problems. I do not see a home run this year or next by any means. But gene therapy will certainly go forward this year and next. It is going to take time to work out major bugs which, hopefully, can be worked out.

Gene therapy is a new way of delivering something. In AIDS usually, but not always, we think about it as delivering a gene, which, when put into a cell, will protect the cell from being infected. But there are other imaginative uses of gene therapy going on–for example, in Seattle, by [Dr. Philip] Greenberg and colleagues–that augment the immune system, let us say. But the approach that we have focused on and the one most people are focused on has been to inhibit HIV from being able to infect a cell. You put a gene in and you say, “Never will that cell get infected.” Now, what cell would you like to put the gene in? Since we know that T cells and macrophages at least can be infected, we would like to get the gene into the stem cell which gives rise to macrophage and T cells. One problem is getting enough stem cells cultured in the laboratory. The second problem is getting efficient transfer of the gene into the cell. Barring that–it works beautifully in the laboratory in small-scale studies–I believe, and I think most people believe this, we would be able not to have to take bone marrow out, work with isolated stem cells, and infuse them back into the patient's arm. This is hardly something that is going to help the Third World. But it would be wonderful if we could just give it the gene once intravenously and, say, go to the stem cell, hit 90 percent of them. If we can do that I think it will be a potential treatment for the Third World because, although gene therapy for AIDS in the Third World sounds like it is too fancy, it is the perfect therapy. A person does not have to keep taking pills all the time. One inoculation and it is over. That is a dream.

It is theoretically doable, but the problems are not solved. In theory, you could draw something on the board and say, “Here is the idea and here is how it should work, et cetera.” But we are not there yet. You can safely predict that it will be in clinical practice next year or the year after. You can safely predict that we will improve the way we target cells, including stem cells. How soon that will be, I do not know. How efficient it will be, I do not know. But, ultimately, this could be one major way to get on top of the problem.

We have also suggested–this has been an idea we have championed in a way–the idea of targeting cellular factors because they do not mutate like the virus and, as we talked about once earlier, the virus needs cellular factors to replicate. It does not readjust itself. It does not have a metabolism. Rather, I should say it “cannot” readjust itself. You cannot put a virus in broth and say, “Go replicate,” as you can bacteria or a parasite or a fungus. A virus will just sit there until it is finished because, as you know, a virus is made up only of genes and proteins, so it needs more of them to reproduce. It gets them from the cell. If you can find things in the cell that you can interfere with without too much toxicity, you may be able to block HIV replication.

To investigate this kind of idea, we focused on hydroxyurea because it is known, available, can be given orally, and is relatively cheap. People know how to use it. It targets a cellular factor that HIV needs to continue its replication. Unless you want me to, I will not go into details on that. It is in clinical trials in France. Some interesting results were reported recently in The Lancet. If I have something to say about a running a clinic, which I will soon, hydroxyurea will be in clinical trials in this state [Maryland]. So will some of the antisense [RNA]. And so will modulation of the immune system with cytokines.

I will come to the last part of what we are doing, and that relates to the HCG [human chorionic gonadotropin] from the anti-KS effect. We believe HCG has much more to offer than that, and it is getting us into hormone research. It is something that I dread because I do not know anything about hormones, and there are many people who do. It is something we will just have to keep learning about.

Rodrigues: You have been telling us about some of the therapeutic possibilities for AIDS. Our understanding of HIV has given us these opportunities to design new therapies. Do you believe that there are other aspects of the basic life cycle and pathogenesis of HIV that we still need to learn about before we can get more therapeutic opportunities?

Gallo: The idea that there is more to learn and that it will give us more ideas for therapy–of course, we are not at the end of the road. One would be the study of some of the so-called “auxiliary” genes like vpr and vpu, things of this kind, vif, nef. All those things are giving new ideas for therapy as we talk. Yes, there is still more basic information that needs to be generated which will give more ideas about therapy. That is not just antiviral therapy, but also with the immune system. But that does not mean that we should not pursue what we know in practical ways with speed.

Harden: We wanted to ask a few questions that were less scientific and perhaps more organizational and political. Various groups have made suggestions about how one might best coordinate AIDS research, and I am sure you recall these various ideas. With regard to intramural research here at NIH, how would you organize it for the optimal outcome?

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