HIV: Racing to Identify a Killer

HIV was one of the most important viruses of the past century. It caused profound suffering, It led to intense political and social confrontations and eventually transformations. And for scientists, HIV posed a complicated set of problems that still have not been entirely solved. On today's show, we're going to focus on the scientists and the science. I'm Jacob Goldstein, and this is Incubation, a show about viruses. In the first half of the show, we'll talk with a virologist.

We start to see those patients. They were young, they were gay, and they had a lot of infections and they were dying.

Like did you see yourself in them at all? Like here of just some young healthy person, suddenly they get sick and die.

Yeah, we had patients with our age. I was thirty at the beginning. Those who were hospitalized died rapidly. They come to the hospital very late in the disease, and within the gay community, I could see progressively some of them with big lymphnods, some of them with the caposis are comma very difficult.

And so what are you what are you thinking when these when these people start showing up with these strange symptoms.

From the beginning, the sign of our infection was there. When you look at the number in blood of cells, you can make the difference between bacteria and virus. Is infection. And we we discuss with the different teams and we start with the ideas that could be a retrovirus, a very specific retrovirus.

Why do you think retrovirus? We should say, by the way, retrovirus is a virus that use is RNA instead of DNA. Why do you think it's that?

So how can I say it was vious.

Alamodo alamode like it was sort of the fashionable virus. It was the it kind of virus, fashionable virus. Yes, you and your colleagues have this hypothesis, we think this is a retrovirus. What is the first thing you do?

We went to see Luke Montagnier and Francos virus and you see in Pastor in.

Situew Luke Montaigne worked with Francois Barressing. You see at the Pastor Institute, these two scientists who will become very famous.

Yeah, yeah, And we asked them, do you think that it's possible to try to isolate the virus retrovirus? And he said, that's a good idea. Maybe we can try. Maybe, Okay, we'll do the work. So we come back to the working group and we decide to take the lymph nodes because they were very big, and to take a blood in a nearly a symptomatic patients.

Okay, So You're at the hospital seeing these patients sick with what you think might be a retrovirus, and you're taking samples from patients at what seemed like different stages of the disease and sending them to these academic researchers at the Pastor Institute.

What happens next fifteen days after Luc Montaignefon and we have something. We have something, We have something.

Front Soise Barre Snusi. That researcher who was working with Montagnier had discovered evidence that suggested a retrovirus was in fact the culprit for this mysterious disease. The team developed a blood test to identify patients with antibodies to this virus. Test allowed researchers to diagnose the virus not only in gay men, but also in IV drug users and hemophiliacs, But the illness was still a mystery, and in particular, even though they knew it was a retrovisvirus, no one

He said, for the first days, no, I can't see nothing. And then after three days he said, come and see. I'm sure there is something.

What is the microscopycy happening in the cell?

He sees the budding of the virus at the surface of the lymphosize.

Uh huh, And so does that mean coming out, going in? What does budding mean?

In that kind of budding is when the virus has been within the cells he has to get out, and he could see free virl particles and he could see also that those particles came from those infected cells. Budding is a Commondi budding.

It's sort of exploding out of the cell or leaving the.

Cell, exactly, the moment of leaving the cell.

That's so this is like a big moment, right. You're not only seeing the virus, but you're actually seeing it as it's.

Leaving the host cell exactly.

Do you remember when you saw that image for the first time.

Ah, yes, I remember very well, because at that time we say, oh, now what we have to do with that. We have to organize everything.

So your response is not Wow, we did it, it's oh my god, We've got so much work to do.

Yeah. You know, in France we say we have the nose in the bicycle, I mean.

The steering the handlebars, just looking at not looking at your head down those to the handlebars.

Yeah, exactly.

And so that's the moment when you're basic saying we found it, we found the virus that is causing this mysterious disease.

Yeah, and a paper with the publish in science.

Meanwhile, in the United States there is another team working to study the disease. It's led by Robert Gallo, a famous virologist at the National Institutes of Health. And this is where a story of discovery becomes a story of a competition, of a fight over who really discovered the virus. But it didn't start out as a fight. It started out as a collaboration.

Luke Montagne decided, because he knows very well Bob Gelou at that time, he decided to collaborate and to cooperate, and he sent samples with the virus to Bob Galu. Okay, can you imagine that?

Well, that's like the ideal of science, right, They're not rivals. They're working together to increase humanity's understanding exactly.

Yeah. Yeah. And then Bob Galou publish a discovery of AS virus.

H huh, you're using air quotes as you say discovery.

Yeah, yeah, in April nineteen eighty four, and he said, we discovers the virus.

Just from Gallo's point of view, what is his claim in eighty four of discovery.

He claims that the virus was not completely identical to our virus, and he says mine is really AS virus in the United States.

So Gallo was saying he discovered the AIDS virus in the United States. From your perspective, your lab already discovered the virus. What do you think when you read this paper?

It was a very difficult period of time for us. And in France he said, you can't imagine. Of course, Bob Gallo is right and your virus is not the right one.

Oh, I would not have guessed that. Wait, even even in France they said that. I am surprised.

Even in France. You know, we were young frenchie. Yeah yeah, those little frenchie compared to the bag Gallo, it's not possible. Bob Gallo is very important in the nine i H compared to us. We are not professor, We were just assistant in labs. We are so young.

What do you think when this is happening and people are saying this you personally, we.

Thought that we had to go more rapidly for the demonstration of our RUS and with particularly with zero logical tests. I'm in the screening with my test.

Yeah, you know, we.

Were working and working and working publishing with US, with Italian, with CDC. We have to work more and more to show that we were right at that time. So we progress a lot with the number of patients which increased. That'side time everywhere.

In nineteen eighty five, the Pastor Institute sued the United States government, claiming that Bob Gallo's team had used the French samples to isolate the virus and create an HIV blood test. The lawsuit was eventually settled, and in April nineteen eighty seven, Ronald Reagan, the President of the US, and Jacques Chirack, the Prime Minister of France, actually held a joint press conference where they announced that both countries

But maybe few years after we had the technology for genome sequencing, and you know, the story is the end of the story. Genetics sequencing of the virus from Bob Gallow's lab and from our LAMB show that the Bob's Gatherous lab was exactly the same that our virus.

After that, genetic sequencing proved that the viruses were identical. Bob Gallow's lab said the whole thing was a kind of a mix up, the result of an accidental contamination. The final verdict in the fight over the discovery of HIV came decades later.

And we waited until two thousand and eight against the Nobel price, and Bob Gallo did not receive the Nobel price. And the people from the Nobel Price, the jury of a Nobel Price, explain us they look for They looked at everything in Bob Gatherous lab, everything in Luc Montagni labs, and they understood very well as the story with a sequencing showing that the virus was our virus.

Bob Gallo is still all credited with important research on the links between HIV and AIDS, and even when the Nobel was announced, Luke Montaigner was quoted as saying that the Gallo team deserved to share. How did you feel when you found out about the Nobel Prize?

Very well satisfied because you know, we started with history in nineteen eighty three and it was a long time ago after, yeah, and it was very important to be recognized even later.

Yes, I mean the Nobel Prize is legit recognition. It's for real, Like if you want to be vindicated in science, it's tough to beat the Nobel Prize.

Yeah. After yeah, after fighting a lot with US people with even in France, it was a Greek moment in Stockholm. But we built a working group with the physicians, semanologist and self biologists in order to try to understand what I want with those patients. And that's a very important point of the story because we were a multidisciplinary working group and you know it's a listen learned. You can't do such a research alone, you can't.

Wonderful, Thank you so much for your time. It was great to talk with you.

Thank you very much.

Christine, whoso has spent the last forty years studying HIV and AIDS, including work on preventing transmission of the virus from mothers to children. She's currently a professor of virology at Paris Descartes University. So can we talk about HIV?

Sure, that would be wonderful.

My guest for the second half of the show is Richard Koup. Richard is the Deputy director of the Vaccine Research Center at the National Institutes of Health. He has spent his career studying and testing HIV vaccines, and, as he explains, creating a vaccine against HIV is this extraordinarily hard problem that goes to the heart of why this virus is so insidious? Why did you become an infectious disease doctor?

You know, when I was in medical school and my training, I noticed that almost all of the different specialties in medicine dealt with chronic illness, and infectious disease was the one specialty where you didn't have to deal with chronic illnesses. What you actually did was you cured people. So people would come in with infections, you gave them antibiotics and they were cured, and that felt very good.

Like Christine lose you. Richard Kaup started his career at the beginning of the AIDS epidemic, and over time HIV would in fact become a chronic disease, but that was in the future.

What we knew then was the genetics of the virus, but we didn't really know much about the immune response, so we were just sort of mapping out what they were responding to.

It was like we knew what the virus was, but we didn't really understand what it did, how it worked.

Yeah, not really, And we knew that for most viruses, in a vaccine, you want to target the envelope protein, the protein that's on the surface of the virus that is used to enter cells, and so that's what most of the first vaccines were directed against.

Which is like very reasonable, right, Like that's what scientists just did with COVID, and it's like that is sort of what's floating around in your body and it's what the immune system sees. So it seemed it's logical that you would want to do that. What happened when when you and other researchers tried that with HIV.

Well, you generated an immune response, so you've got antibodies against the envelope protein.

Seems good, that's what you want, Yeah.

But those antibodies didn't do anything, they didn't neutralize the virus.

What was the next thought, What was the next idea?

The thought then was, well, what we should do is stimulate T cells, so T cells recognize virally infected cells and kill them. And there were there was a lot of data to suggest that people who were long term non progressors, so these are people who are infected with HIV but they don't progress to full blown AIDS, they had really good T cells that were attacking the virus.

So basically there is this universe of people who have HIV, who are HIV positive, but who are not getting really sick. And this is an era when most people who get HIV get AIDS and die essentially right, get very sick. And so you look at these patients and you see that there is a particular kind of a cell in their immune system that seems to be fighting the disease.

Is that right, That's absolutely correct. You hit the nail on the head there. And so with this insight, people said, what we should do is stimulate with a vaccine, not antibodies, but CD eight positive T cells.

So basically, like the first idea was sort of a classic vaccine idea like let's create a vaccine based on antibodies that didn't work, and so then the second idea is to stimulate T cells, this particular part of the immune response that vaccines don't usually deal with.

Instead, it was felt that those vaccines may not keep people from getting infected, but if they had the vaccine and the people got infected, that they may all become long term non progressors, so they wouldn't get sick.

Which is actually what you care about, right, what you want is for people to live long, healthy lives.

That's absolutely correct.

So you do this trial and what do you find?

It did not do what we had hoped it would do.

And what year more or less is this.

We've been doing this for twenty years of efficacy trials, and seven different trials have been done and none of them have shown really good protection.

So a long time into the history of this disease. This is decades of work in and if you'll allow me this sort of dumb journaloius question, what was that like?

It's terribly disappointing. You know, you put a lot of effort into this, your hoping that finally something will work against this illness. And when it doesn't work at all, you're really back to square one. So it's extremely disheartening.

Why is it so hard to vaccinate against HIV?

So unlike most viruses, most viruses enter cells of your body, they use the machinery of those cells to replicate, and then they leave your body and they're gone. They leave, and you're no longer sick. When they're not there.

You get a cold and then you get better.

Right, and there's no cold virus left in the cells of your.

Body because your immune system destroys all the virus, right.

And so with a vaccine, all you need to do, actually you don't need to prevent the infection. All you have to do is knock down the amount of virus it's replicating to decrease your symptoms until the virus goes away.

Okay.

HIV is different in that it infects certain cells of your body and it actually integrates its genome into the genome of those cells and it never goes away.

Huh.

I like to think of it like playing whack a mole. So it's basically hibernating in those cells, and then the virus will will pop out every now and then, and you need to try and knock it down, and our antiretroviral therapy that we give to individuals doesn't do anything to the virus that's sitting there hibernating. It's only when when it reactivates and pops itself up that the antiretrovirals have any effect.

This is why the antiretrovirals can keep you from getting sick, but they cannot cure you per se.

Yeah, because it it'll never get rid of all of those hibernating viruses.

Uh huh. So what does that mean from the point of view of developing a vaccine.

That means that you have to block every single infection from occurring.

That seems wildly difficult. Tell me, give me some hope. Now I am here sitting here thinking there is no way. You know, but I don't know anything. Tell me why there is a way.

So certain individuals who are infected with HIV develop what we call broadly neutralizing antibodies. So these are antibodies that can neutralize seventy eighty ninety ninety five percent of hivs that are circulating in the world.

These are just patients who have HIV who have this particularly robust natural immune response absolutely.

So we know two things. One that there is a way that the immune system can develop these types of antibodies. The other thing that we know is that these antibodies target multiple different sites on the HIV envelope protein. So there are multiple targets on the HIV envelope that can be used in the vaccine to stimulate these types of antibodies.

And as I understand it, that technique works to protect people against some strains of HIV, but not all, right, And so what percentage of strains were people protected against in that trial.

For this antibody, It was it was about thirty percent of viruses.

Okay, so that not that broadly neutralizing in that instance.

No, but this was one of the very first broadly neutralizing antibodies that we had that we did this trial with. There are much broader and better neutralizing antibodies that are available now. But what this is also showing us is the roadmap of if we can develop a vaccine that will recapitulate the development of these broadly neutralizing antibodies in

So the basic idea is, like, we have these antibodies that seem to work, let's develop a vaccine that can induce people to develop these antibodies.

Yes, that's exactly it. So there's still many big hurdles to get over, but the initial studies have shown that we can actually get the immune cells in the body to start producing the correct type of antibodies.

These broadly neutralizing antibodies that we want.

Well, they're sort of the precursors of the broadly neutralizing anivites.

They're on the JV team. With some work, they can make the varsity.

We need to shepherd them along, mentor them, tutor them, and get them to be broadly neutralizing.

So still a long way away. Clearly, it's a profoundly difficult virus to vaccinate against. Drug treatment for HIV, on the other hand, has been quite successful, right, and now you can do prophylaxis with drugs, which is great. Obviously, it reduces human suffering a tremendous amount. Do we need vaccines less because the drugs work so well.

It gives us a bit of a breather in that we know that there are other ways to protect people who are at risk of HIV infection. But there's a lot of healthcare delivery that would need to go into protecting the world against HIV in the absence of a vaccine, and you need the infrastructure to do that, And in parts of the world it's hard to get to the people to actually give the medications that frequently. A vaccine just makes it much easier to provide that protection.

And it seems like there is at least some correlation between parts of the world where it's hard to get people HIV drugs all the time and places where kind of suffering from HIV is high.

Absolutely.

It's interesting how science generally is more often than not the story of things not working. Right. We tend, you know, in the media, say to focus on things that work, but I feel like in the aggregate, science is things not working. And I'm curious, you have spent a lot of time working on things not working. Sort of what have you learned from working on such a hard project.

The most difficult problems are the most interesting to work on.

Feel like you're generally an optimistic person.

I hope so. I don't think I I'm as optimistic as some people I know, But you know I'm not a Debbie downer.

Yes, you know.

I think if I were on my own trying to do this, it wouldn't work. But the community of the HIV vaccine researchers sort of keep each other optimistic and moving forward.

Thanks very much for your time. I really appreciate it.

It was my pleasure.

Thank you very much. Richard Taut has been researching HIV for thirty five years and working on vaccines for twenty five He's the Deputy director at the Vaccine Research Center at the National Institutes of Allergy and Infectious Disease at Anahe thanks to both my guests, Christine Rouziu and Richard Kaup next week. There's lots of mosquitoes in the world, and not all of them are welly good at spreading disease, butadies Agypty is one of the best mosquitoes viruses and