|Office of NIH History|
|Previous Page (6 of 6)||Transcripts|
Rodrigues: One of the things I wanted to get back to was something you talked about at the very beginning about the species-specific nature of retroviruses. Of course, one of the questions that comes up is how is it that chimpanzees can produce the virus but not get sick?
Rodrigues: Do we understand exactly what is happening with these viruses in terms of why they are so species-specific?
Rodrigues: From an evolutionary point of view you would think that viruses would do better if they were less fastidious about the particular type of species they infect, but yet they seem to be extremely fastidious about what animal they infect.
Gallo: It is an interesting question about the species-specificity of viruses and whether or not their evolution would be better if they could jump from species to species willy-nilly. This is an interesting point. But if a virus is highly fatal and it is jumping from species to species, it will run out of things to infect to keep itself going. If it does not have to, if it survives within a species, it need not evolve to be able to go to other species.
In the wild maybe things are a little more separate than they are here as we domesticate things. As we domesticate things it seems maybe there has been more jumping of species by microbes from one animal to another animal type.
Viruses are not always highly species-specific. Take rabies. It can jump into many different animals. But you are right when you say that I have said that retroviruses are generally species-specific. It is unusual for a retrovirus to go from one species to another. But it has happened in evolution that a retrovirus will jump species. There are many cases where we can document that.
But at any given moment in time, if you have in hand all the retroviruses that we study in the laboratory, and you say to a mouse virus, “Can you become a leukemia virus of cats,” that is, the mouse leukemia virus is to become a leukemia virus of cats, the answer is generally no. So there is quite a bit of species restriction.
Now, HIV can infect chimpanzees. That is true. You wonder why they do not get disease. First of all, HIV does not replicate as well in chimpanzees as it does in humans. That may be one of the critical reasons. But there are a host of things that people have found that correlate with the chimpanzee not getting disease, not just that the virus does not replicate as much: there seems to be a greater cytotoxic T-lymphocyte activity; the chimpanzee does not have herpesvirus-6, that could, I think, be a cofactor in progression–I do not want to use that as a major argument–but there are differences in the chimpanzee that could lead to an all day discussion of the five, six, or seven reasons why the chimpanzee might not get sick from HIV.
I do not know if this is answering your question, but I cannot give you a better explanation of why, in the evolution of a virus, it would not be better if it jumped species. It makes sense that it would, and some viruses do. But I repeat, if it was a virus that caused real problems and jumped species a lot, it might run out of things to infect. But the reason it is often species-specific resides in the receptors on cells. For example, HIV needs the CD4 molecule and the CD4 molecule, as the virus needs it, happens to be on our cells and on those of chimpanzees, but it is different enough that the virus does not penetrate efficiently.
That is not the whole answer. If you put CD4 in a mouse it still does not get infected and replicate well. Why is that? It seems that there are also other factors, maybe secondary receptors or maybe cytoplasmic factors, that are needed to complete the virus replication cycle, and most likely both.
Rodrigues: My next question has to do with the question of the ability of HIV to mutate. From what I have read, it seems that when you look at HIV relative to some other viruses it has a very high, or higher than average, rate of mutability.
Gallo: Yes, and no. You asked me if HIV has a lot of variation? Yes. You asked me if it has more mutability, or if its mutation rate is greater, than other viruses? Actually, it is not that much more impressive, or maybe not more impressive at all, than a number of other viruses, especially, according to the analysis by [Dr.] John Coffin at Tufts University, who is the best thinker on this that I know, but it is because of the number of its replication cycles. Remember, it is a persisting virus and it is replicating much more than we thought. Every time it goes through a replication cycle it has golden opportunities to change by recombination because it integrates, by mistakes through reverse transcriptase, and by more complex mechanisms that we will not get into now.
Rodrigues: Because of this issue of the mutation of HIV, some people have suggested that it could possibly mutate into a form that would be more or less pathogenic. I think you addressed that question in your book. But another related question that I have has to do with mutations of HIV, what are the implications of the mutation? Is it just its antigenic presentation, as you might see in influenza, or is it something more fundamental?
Gallo: Mutations in HIV, depending on where they are, even very subtle ones, even of a single nucleotide, can sometimes lead to dramatic biological differences in a variant of the virus. For example, in laboratory studies it can make a virus go more towards T cells or more towards the macrophage. It can make the virus be more or less cytopathic, in vitro. It can make the virus replicate faster. It can make the virus replicate more slowly. Theoretically, this should make great differences, in vivo, and it almost certainly does.
Very subtle mutations in the wrong place, or right place, depending on the outcome, can make dramatic biological differences in the virus. It is not so much antigenic variation, because there is very little antigenic variation. The variation is in the behavior of the virus.
This gives rise to the notion that we might create an HIV that is easy to spread all over the place. At an international meeting, Dr. Montagnier was saying yes to that question while I was, at the exact same time, saying no. I believe that that is exceedingly unlikely because to harm the immune system the virus has to keep some of its guns exactly the way it has them. If it mutates to become casually transmissible, which retroviruses virtually never do, it would certainly lose its ability to target the CD4+ cells. The virus cannot have it both ways. You cannot make a giraffe, a lion, or a lion a giraffe. You may change the spots a bit on the lion's mane, or the lion's color, or something like that, and in the case of HIV you would see many different colored lions, lions with bigger, thinner paws, and faster and slower lions, but it is not going to make it become a giraffe. I do not think there is the danger that this is going to evolve into a pathogen that is casually transmissible, the nightmare of nightmares.
On the other hand, I have no doubt that HIVs now in the population have substantial variation in their ability to cause disease at certain rates. In other words, I feel confident that some of the reasons for long-term survivors–not the only reasons–and also for short-term survivors are the dosage of the virus and the very virus type that the people get infected with. It is self-evident. Look at HIV-II. It is less pathogenic. HIV-II is 50 to 60 percent different from HIV-I. Well, there are HIV-Is that are 10 to 20 percent different from each other. Is not that also likely to make the virus biologically different to some degree in its ability to cause disease and its rate of causing disease, in short, its virulence? I believe so.
|Previous Page (6 of 6)||Office of NIH History | NIH| DHHS|