Why don't we have an HIV vaccine?

Tiny Matters

We had a vaccine for COVID-19 within a year of identifying the virus that causes it, yet still don’t have one for HIV after 40 years of research. Why is that? On this week’s episode, Sam and Deboki cover HIV’s history and spread, how it causes AIDS, and the tiny things it does that have allowed it to evade potential vaccines for decades.

Transcript of this Episode

Sam: In the early 1980s, doctors in the United States started seeing something unusual and alarming: young men, previously healthy, were showing up to hospitals sick and dying of diseases that just didn’t make sense. Diseases that were only really seen in people much, much older or in people with compromised immune systems. We now know that doctors were witnessing the start of the AIDS pandemic.

Deboki: By 1984, researchers had figured out that AIDS—acquired immunodeficiency syndrome—is caused by a virus called HIV. And they knew that the best way to stop it would be with a vaccine—I mean there were already vaccines for loads of other viruses like polio and measles and the flu. So by 1987, the first clinical trial for an HIV vaccine in the US had begun.

Sam: But today, almost 4 decades later, there’s still no vaccine. And AIDS has killed over 37 million people. So why don’t we have an HIV vaccine? I mean, we had a COVID-19 vaccine less than a year after the virus that causes it was discovered.

Sam: Welcome to Tiny Matters, a science podcast about things small in size but big in impact. I’m Sam Jones...

Deboki: And I’m Deboki Chakravarti. Today on the show we’re talking about human immunodeficiency virus—aka HIV—its history and its spread, how it causes AIDS, and the tiny things it does that have allowed it to evade potential vaccines for decades.

Sam: This is a pretty heavy episode—heavier than most we’ll do—but this topic just feels so important to cover. That being said, we wanted to warn you up front that there will be some conversations that might not be appropriate for young listeners.

For this episode, Deboki and I reached out to Stosh Ozog. He’s a virologist and Resident Physician at the University of Washington and has done a lot of HIV research. And, at the start of our chat, he told us something that was kinda shocking.

Deboki: Oh yeah, definitely shocking.

Stosh: The thing that surprises a lot of people is HIV has actually been with us we think as far back as the 1910s or the 1920s—you know, the earlier parts of the 20th century actually. So in the 1930s and 1950s, there would be these little outbreaks in parts of especially Africa that nobody could really describe or explain what was going on at the time, but it's been theorized that some of those cases might actually have been from early HIV infections.

Sam: Before we get into why scientists think HIV has been with us for over a century, we’re going to take a few minutes to cover the basics: What is human immunodeficiency virus? Deboki, do you want to kick this one off? I know you’ve actually studied HIV a bit before, right?

Deboki: Yeah, I did some work in a computational lab when I was in college where I studied how mutations in HIV spread across a population.

Sam: Ok, so, tell me about what makes HIV...HIV.

Deboki: So all viruses have some form of genetic information that they use to replicate once they get into our cells. HIV’s genetic info is stored as RNA, just like with SARS-CoV-2, the virus that causes COVID-19. Unlike SARS-CoV-2, HIV is what’s called a retrovirus. So when it enters a cell it releases its RNA along with an enzyme that’s called reverse transcriptase.

Sam: Reverse transcriptase turns RNA into DNA, which is then referred to as “proviral DNA or provirus” which is then integrated into the DNA in our cells. The virus has another enzyme for this, called integrase. The integrase essentially cuts bits of our DNA and pastes in the HIV DNA. In other words, HIV becomes...part of us. But it doesn’t target /all/ of our cells. It targets cells in our immune system—maybe most importantly our CD4 T cells.

Deboki: CD4 T cells are often called "helper" T cells because they trigger other immune cells to fight off foreign invaders like viruses or even a cancerous tumor that might be starting to grow. And I cannot stress enough how important CD4 cells are in keeping us healthy. So HIV hijacks these cells and uses them to multiply and spread. And over time, the virus kills those CD4 cells, which is why AIDS is usually diagnosed based on CD4 cell count. If the count is really, really low that’s a sign that someone’s HIV infection has progressed to AIDS.

Sam: And, at that point, a person’s immune system is too weak to fight off a bunch of diseases or infections that a healthy person is probably able to, like Pneumocystis jirovecii pneumonia or PJP, which is caused by a fungus that commonly hangs out in our lungs and wouldn’t be an issue if a person weren’t immunocompromised. PJP was seen a lot in early AIDS patients, as was Kaposi sarcoma, a type of skin cancer.

Deboki: So let’s talk about the current state of things. Sam, what are people’s options for dealing with HIV?

Sam: Ok, so because HIV inserts itself into the DNA of our cells, there isn’t a way to get rid of it, but there are antiretroviral drugs—sometimes referred to as the anti-HIV "cocktail" of drugs—that will block that reverse transcriptase enzyme and keep the virus from from being able to replicate. And, actually, for groups of people who are considered at higher risk for contracting HIV—like people who may be using injection drugs, or sex workers—there are antiretroviral drugs given to prevent HIV. This approach is called pre-exposure prophylaxis, which you’ve maybe heard referred to as PrEP.

Deboki: And PrEP works incredibly well BUT there isn’t access to these drugs in some parts of the world, like regions in Sub-Saharan Africa, where you see the highest percentage of HIV infections. That inequality in access means people in those areas are far more likely to get infected and to have that infection progress to AIDS.

Sam: So now let’s get into the history of HIV: How scientists have pieced together where it came from.

Deboki: HIV mutates a lot to evade our immune system. Every time it mutates it creates another point on its viral family tree. So through genetic analyses and mathematical modeling, scientists are able to ask questions like “when and where did this pandemic start?”

Sam: In the places where the virus has been replicating the longest, HIV will have accumulated the greatest number of genetic mutations. It turns out that that place is the Democratic Republic of Congo, in its capital—Kinshasa—which brings us back to Stosh talking about HIV in the early 20th century.

Stosh: The thing that surprises a lot of people is HIV has actually been with us we think as far back as the 1910s or the 1920s—the earlier parts of the 20th century actually. In the 1930s and 1950s, there were these little outbreaks in parts of especially Africa that nobody could really describe or explain what was going on at the time, but it's been theorized that some of those cases might actually have been from early HIV infections.

But the earliest known infection—earliest verified case—was actually taken from a blood sample from a man who was in what's now the Democratic Republic of Congo back in 1959.

Deboki: Now you might be wondering, where did early-1900s HIV come from? In short, other primates—likely chimps. This is a case of one species transmitting a virus to another species—a concept that’s probably not all that unfamiliar because of COVID-19. As it turns out, there are non-human primates out there with a very closely related virus called simian immunodeficiency virus, or SIV.

Sam: And more recently researchers figured out that a perfect, terrible storm of events probably allowed SIV to cross over to humans where it ultimately evolved into HIV. That terrible storm all started with...colonialism.

Deboki: In the 1920s, Kinshasa was better known as the Belgian colony Leopoldville. There were a bunch of labor camps set up and a lot of people to feed.

Stosh: In order to provide food for that huge labor force, there's some evidence that a lot of what was being done was going out into the jungles of that time and killing or hunting animals that would provide some food for that forced labor workforce. And one of the biggest sources you can imagine in that area is actually apes or, you know, different kinds of monkeys. And you know, that's an area that has chimpanzees that are in very common contact with humans.

Stosh: People are killing chimpanzees and they're getting in very close contact with their blood, because oftentimes the butchering for this is done in the field. So meat was actually dressed. And so you can imagine somebody is out there and is cutting up a chimpanzee that they'd just shot and gets a little cut on their hand or cuts their finger on a shard of bone. And then that monkey was infected with not HIV, but an SIV that was awfully, awfully close and then was able to infect and enter into that person. And that idea is called the sort of the hunter theory or the hunter hypothesis.

Sam: So you have forced labor camps, which require feeding more people, which increases the hunting of primates, and then you also have sex camps—forced sex—which meant a sexually transmitted disease like HIV would have more opportunities to spread, and then on top of that you have this new thing called travel.

Stosh: Around 1910, 1920 you are also getting this huge industrial explosion in Africa. And the transportation networks in that part of the world were really, really expanding. So you suddenly have rail and now people are able to travel hundreds of miles and repeat the cycle. And so, whereas we thought that probably people have been exposed to SIV in that part of the world for hundreds, even thousands of years, there was never enough ability to travel to set off a pandemic.

Sam: So now let’s fast forward to the US in the early 1980s. In 1981 the CDC published a report where they described that rare lung infection I mentioned earlier—PJP—in five young, previously healthy men in Los Angeles. These men also had other unusual infections that clued doctors into the fact that their immune systems weren’t working properly.

Two of the men had already died by the time the study was published and the other three died not long after. With these healthy men suddenly getting sick, seemingly out of nowhere, people panicked.

Stosh: Kids weren't allowed to go to school. People weren't allowed to share swimming pools, people were told they couldn't work because we really didn't have any idea of how HIV spread at that point. We just knew it was very, very deadly. It’s one of the most deadly viruses we’ve ever found.

Deboki: And that fear meant that discrimination toward patients with HIV or AIDS grew.

Stosh: HIV being something that predominantly affected gay people, especially gay men was you know, people call it gay cancer. They thought it was God's punishment on that lifestyle.

Sam: Although people may discriminate others based on sexual orientation, HIV does not. Anyone can contract HIV, and because it lives in the blood, semen, and vaginal fluid, the main modes of transmission are sex and needles sharing, but it can also be passed from one person to another through blood transfusions, during pregnancy, and through breast feeding. It does NOT spread through general contact—things like hugging, dancing, or shaking hands. It also doesn’t spread through the air like COVID does. But in the early 1980s people didn’t know that yet.

Stosh: A lot of people were really afraid to spend time doing research on this because it was so dangerous. But that being said, it was obviously a lot of benefit to society if you were the person who discovered what was the cause of AIDS. There were three groups, basically, that were kind of in the lead for discovering it.

Deboki: Ok, so we’re going to give you a quick rundown on those three groups, starting with Luc Montagnier’s group at the Pasteur Institute in Paris. In 1983, they cultured T cells from a 33-year-old French patient with symptoms that seemed to indicate he had AIDS. They were able to isolate a virus from those T cells that they then used to successfully infect healthy T cells in a petri dish. That virus ended up being HIV. In 2008, they were awarded the Nobel Prize.

Around the same time, in 1984, you have immunologist Robert Gallo and his team at the NIH also isolating HIV, but from a larger group of patients. And a third team of scientists in California also identified HIV and further strengthened the link between the virus and AIDS.

Sam: Jay Levy from the University of California, San Francisco, who was part of that California team, actually has some of some of the equipment he used for that research on display at the National Museum of American History in Washington, DC.

Deboki: No way.

Sam: I know, right? It’s super cool. So you have 3 teams independently identifying HIV all within a 2 year span. That is pretty incredible. But even though there were obviously scientists working hard to understand this deadly virus, the US government was coming under fire for not publicly acknowledging its existence. It took Ronald Reagan—the president at the time—until 1985 to mention AIDS publicly, and until 1987 to really talk about what was being done to stop the AIDS pandemic. 

Deboki: So now that we know what HIV is, where it came from, and how it causes AIDS, the question that still remains is: why isn’t there a vaccine for it? And, before Sam and I dive in, we want you to keep in mind that we’re only going to be covering the science side of things, but we think it’s important to acknowledge that the science behind HIV is not the entire story.

Sam: Yeah, there have been so many societal influences here and so much nuance that really that alone could be an entire podcast series.

Deboki: Absolutely.

Sam: So let’s break down how HIV is nothing like COVID. And by that I mean, let’s have Stosh break down how HIV is nothing like COVID.

Stosh: We're amazed by these fantastic vaccines that have been produced for SARS-CoV-2. And it's like a completely legitimate question as to why we've been studying HIV for 40 years and we still don't have one. And it kind of comes down to some key differences between COVID and HIV. So HIV, because of that trick that we talked about a little bit where it can put a piece of its own DNA into our DNA, it really is a master hider. It has the ability to stick around and because it infects T-cells and many types of T-cells live for decades and decades, as long as that cell is still alive, that virus is still alive. And there's been some really well done studies where they've looked at, what's like the minimum number of infected cells that you have to have to keep an HIV infection going, and it's a bonkers number. It's like one provirus is enough to re-infect the whole person. So we have to be almost perfect in order to wipe out HIV from somebody.

And then the other thing that's really challenging about HIV that we didn't have with COVID: we talked a little bit about how much diversity there is within HIV and the amount of genetic diversity and the amount of new mutations and evolution that happens with HIV within one person is enormous. Basically there's more diversity within one person than there is globally with something like the flu. So all the flu mutations in the world going on at one time is less diverse than all of the mutations that are going on in one person with HIV, which is just kind of bonkers. And it sounds like a problem for the virus, but actually it's a great strategy if you think about it because, you know, viruses work in swarms and they don't really care if one of their members gets picked off. It's more about that the hive survives.

If you make a million different or a billion different types of HIV and one of them gains a trick that makes it better able to avoid the immune system, then that gets picked up. It's natural selection in its most pure form basically. And that virus will then carry on and will become the new source of all the other viruses that happen in that person. And one of the biggest tricks that HIV is constantly doing is that it's trying to avoid and hide the parts of itself that are most frequently recognized by the immune system.

Vaccines work by exposing our immune system to just a little chunk of a virus or a bacteria, and basically saying, hey, look, this is the bug that we're hunting for, this is what the immune system needs to learn how to attack so that when it sees the real thing, it knows exactly where to go and how to kill off the bad bug.

Sam: With HIV that has been a huge challenge, for all of the reasons Stosh just mentioned. But there are people out there who might have the answer.

Stosh: You know how I mentioned that HIV is a hundred percent fatal if untreated? That’s not actually true. It turns out there's actually these rare individuals who are able to fight off HIV infection, and maybe they don't get cured, but they never seem to progress to the point where they develop AIDS or develop those infectious diseases that most of us normally can fight off.

So those folks are able to produce antibodies that seem to have some weird and special tricks where they're able to actually get in and bind onto those parts of HIV that it requires the most in order to replicate. It's a bit of an arms race where the virus is evolving to escape those parts and the immune system, in particular your B cells, are evolving to make antibodies that can neutralize the most sensitive parts of the virus. So now what we're hoping to do, and what's been really challenging, is to come up with a vaccine that basically teaches everyone's immune system to behave like those rare people that are able to fight off the virus.

Those antibodies are called broadly neutralizing antibodies or bNAbs. And the goal for a long time here now has been trying to figure out a way to make a vaccine that gives everyone bNAbs, which would be awesome. As of yet we have not succeeded so far. Lots of work being done, but that's the holy grail for now.

Deboki: Although creating a vaccine that would allow us to produce these bNAbs is, like Stosh said, the holy grail for HIV research, it’s not the only thing people are working on. Some researchers aren’t working on a vaccine at all, or even other approaches for how to prevent HIV. They’re trying to cut HIV out of cells once it’s already there.

Stosh: So, you know, CRISPR is this fantastic technology that's come out in the last, um, five to 10 years, which basically has taken over biology. And it’s this really excellent tool—we always say it allows sort of a copy-paste function in the genetic material—you can use it to very specifically turn off or even turn on or cut out sections of DNA. So people have thought of all sorts of strategies of...how can we chop the virus out? How can we reactivate the virus so that it gets noticed by the immune system and cleared by the immune system? And all of those strategies haven’t worked, but with the discovery of CRISPR, there's some evidence and some excitement of thinking, hey, why don't we just try and cut the virus directly out of cells? And that potentially might achieve that long goal of being able to remove the reservoir of the virus from people's immune cells. It's a big challenge, but they're trying it.

Sam: In September, 2021, the FDA approved the first CRISPR-based gene therapy for people with HIV. So there are exciting things happening, but it’s hard to blame someone for being pessimistic about scientists ever being able to cure HIV or prevent it with a vaccine, because they’ve been trying and failing since the 80s. I mean, an HIV vaccine just failed out of phase 2 clinical trials in the fall of 2021.

Deboki: But Stosh told us that, even though defeating HIV is still a battle scientists continue to fight, there have been many victories along the way.

Stosh: As a lay person I would definitely look at it and go, hey, scientists have failed at this for, for many years. And I think I would kind of turn that around and say, HIV has kind of been like the big tutor of immunology for our scientific understanding of how the immune system works for the last like 30 years or so 40 years. I can point to you a dozen different discoveries and even to this day, I would say the COVID vaccines would absolutely not have been possible if we hadn't done this much research and spent this much time on trying to fix this one virus. I mean, HIV has killed at this point 36 million people, roughly, globally and its history. And COVID has now killed about 5 million people. It's shocking how much death and destruction viruses can cause, but HIV has given us, finally, the tools to be able to do something about it.

Sam: There is so much to learn about with this virus. I mean, as I was doing research I think I considered taking this episode in, possibly, 5 different directions? But I hope that you, our listeners, feel like you got a solid idea of why this virus is so difficult to defeat and are leaving with some hope, like we are.

Deboki: Thanks for listening to Tiny Matters, a production of the American Chemical Society, a non-profit scientific organization based in Washington, DC. Tiny Matters is hosted by me, Deboki Chakravarti, and Sam Jones who is also our executive producer and audio editor.

Sam: This week’s script was edited by George Zaidan and was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli, and our artwork was created by Derek Bressler. Thanks to Stosh Ozog for chatting with us.

Deboki: If you haven’t rated and reviewed us on Apple Podcasts, Spotify, Stitcher, Audible, or wherever else you listen, please do!

Sam: Click that plus sign, that follow button—that is how people learn about us, and how we can continue to make episodes...

Deboki: And how we can keep exploring the tiny things that matter.

Sam: We’ll see you next time.


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