If you’re looking for the virus that’s challenged scientists the most in the last 40 years, HIV is it.

For a while, every time we’d develop a new treatment for it, the virus would just mutate so the drug didn’t work anymore. And even though the worst of the pandemic is over in the US, nearly 5,000 people around the world get infected with HIV every day, and we still don’t have a vaccine, or a cure.

But in just a few decades, we’ve gone from knowing nothing about HIV and AIDS to being able to manage and control the disease. Today, with the recommended treatments, someone who’s HIV-positive is expected to live nearly as long as someone who’s uninfected. And researchers are working on all kinds of new ideas to kick even more virus butt, including potential cures.

When the AIDS pandemic was getting started back in 1981, we didn’t know what caused the disease, and there certainly weren’t any drugs to treat it. The most doctors could do was to treat the infections patients developed because the virus had killed off so many T cells that they were left with basically no immune system One of the very first drugs that showed promise against the HIV virus itself was suramin, a medicine already being used to treat tropical diseases. It reduced the amount of virus in cells grown in petri dishes and in patients’ blood.

But in a small clinical trial, it didn’t help patients at all, and it actually made them sicker because the drug was pretty toxic. Labs then started to test old compounds for anything that might work, and eventually, they found something. It was called azidothymidine, or AZT.

It had been a candidate for a cancer drug back in the ‘60s, but it never really went anywhere. Now, it seemed to keep HIV-infected cells alive longer, at least in the lab. Excited scientists rushed AZT into trials with patients, including a placebo-controlled trial, which investigators decided to end early because the drug worked so well.

Although the trial had a lot of flaws, patients getting AZT had more T cells and were much less likely to die. In March of 1987, the FDA approved it, making AZT the first AIDS drug in America. But it was not cheap, and it came with a bunch of side effects, like anemia, muscle weakness, nausea, heartburn, insomnia, and heart and liver damage.

AZT works against HIV because it blocks reverse transcriptase, the enzyme that copies the virus’s RNA-based genome into DNA. But AZT also does something similar to a human enzyme, which causes some of those nasty side effects. Doctors eventually realized that a lower dose of AZT could get rid of a lot of those problems, but the drug had an even bigger pitfall: it only worked for a limited time.

After a while, the levels of virus in the person’s blood started to tick up because it had mutated in a way that meant AZT couldn’t block reverse transcriptase anymore. And that’s the major challenge with treating HIV. It develops resistance to drugs really easily, because it tends to make a lot of mistakes when it’s copying its genome.

Most of the time these mistakes are bad for the virus, but every now and then, the mistakes are helpful. Over time, and with selection, HIV will mutate to get around whatever drug you throw at it. But!

As scientists would soon discover, there is a way to fight back. You just need to combine a bunch of different drugs that can target the virus at other stages of its life cycle. Like the first protease inhibitor, which was approved in December of 1995.

Proteases are enzymes that cut proteins into smaller pieces, and HIV uses one to make a lot of the proteins it needs, including the proteins it uses to infect new cells. So with a protease inhibitor, the virus is still making new baby viruses, but they can’t do much. On their own, protease inhibitors weren’t much better than AZT.

They also had some pretty severe side effects, and only worked until the virus mutated. But now doctors had drugs that targeted two different parts of the HIV life cycle. Which meant that they could combine them, making it much harder for the virus to mutate to escape both drugs.

That changed everything. In 1996, doctors started giving patients these combo cocktails, made of at least two, and soon three or four drugs. They called it highly active antiretroviral therapy, or HAART, because it worked so much better than the individual antiretrovirals.

Patients started living longer. The levels of virus in their blood went down, and stayed down, and their T cell counts stayed high. Today, it’s often just called antiretroviral therapy, or ART, because it’s the standard treatment.

We now have dozens of different drugs that can make up that cocktail, many with fewer and less severe side effects than before. This is the breakthrough that changed HIV infection from a death sentence to a chronic disease. It’s also helped with preventing the spread of HIV, because ART is now so effective that the amount of virus in patients is often undetectable.

Not only does that make the infected person feel better, but it’s also much harder for them to spread the virus to others. Some of the most compelling evidence for this comes from a 2016 study that monitored 1,000 gay and straight couples for HIV transmission. One partner was HIV-positive, but on ART and didn’t have much of the virus in their blood, while the other was HIV-negative.

The couples had sex, and didn’t use condoms. Normally this would be a recipe for disaster. But none of the HIV-positive people passed the virus to their partner, despite 58,000 condom-free sex acts.

That’s not to say that you shouldn’t use a condom, because there are still lots of things that can go wrong, not to mention the other reasons they’re important. But it’s still some pretty solid evidence that treatment can also double as prevention. So the more people who can be put on ART, the better... not just for them, but for everyone.

Researchers have taken this idea a step further with what’s called pre-exposure prophylaxis, or PrEP, where people who are at high risk of infection also take antiretrovirals. Studies have found that people who take a daily pill containing two antiretrovirals have a 90% lower risk of contracting HIV from sex, as long as they take it consistently. Which is actually one of the biggest problems in the HIV world.

Things like side effects or trouble remembering when to take which pills can sometimes make it hard for people to stick to their medication schedule. But PrEP only works if the drug is in your system. If you skip a dose, there isn’t enough of it to keep HIV from getting a foothold.

And for someone with HIV, as soon as they stop taking their proper dose, even if they have almost no virus in their entire body, HIV will start to come back. By letting the virus replicate, even a little, it could mutate, and because some of the drug is still around, it’s the perfect environment to select for a drug-resistant virus that may be impossible to treat. The reality is, as good as antiretrovirals are, they can’t eliminate every single virus, so an infected person has to take the drugs exactly the right way for the rest of their life.

That’s why many researchers still want to find a cure. There are two main types of potential cures: a sterilizing cure and a functional cure. A sterilizing cure is what you would think of as a cure: total eradication from the body with absolutely no virus left.

With a functional cure, on the other hand, the person would basically be in remission. They could stop taking antiretrovirals, but somewhere, deep inside them, they’d still have a small amount of the virus. Most researchers are focusing on a functional cure because it turns out a sterilizing cure is extremely difficult.

In fact, it’s only happened for one person: a man named Timothy Brown, aka the Berlin patient. He was HIV-positive and also had leukemia, so doctors had the idea to try to treat both with a bone marrow transplant using cells from an HIV-resistant person. HIV uses a surface protein called CCR5 to enter cells, and some people naturally have mutations in this protein that make it hard for HIV to infect them.

Doctors gave Brown chemo and radiation to kill off his original immune cells, and then transferred in those special bone marrow cells. And to this day, he’s remained HIV-negative, without having to take antiretrovirals. Technically, we don’t know for sure if he’s totally virus-free, but so far, so good.

Now, as amazing as that procedure was, scientists aren’t exactly sure why it worked. It might have been because of the special cells, but it also could have happened when the immune cells from the donor attacked and killed off Brown’s immune cells, along with the HIV inside them. In any case, we can’t do it for everyone because bone marrow transplants are super risky; lots of people die from them.

And if those HIV-resistant cells are critical, there’s not exactly a surplus of them lying around. So right now, a sterilizing cure doesn’t look likely. A functional cure is much more promising, and researchers are looking at a bunch of different strategies.

One thing they’ve tried is giving antiretrovirals extremely early on. This sometimes works for patients for many years, even a decade or more. But many people relapse, and have to go back to taking medication.

It would also be great if we could get the immune system to attack HIV and do the work the antiretrovirals do now. The problem is, HIV is very good at hiding. The virus stays hidden in cells called latent reservoirs, and it doesn’t try to replicate in those cells, which means antiretrovirals have no effect.

So, even though the virus isn’t causing any harm, it’s still there, and it could become re-activated at any time. One possible way around this is to deploy CRISPR, the gene editing tool, to change the person’s CCR5 proteins. The virus wouldn’t be able to infect new cells, so even if it re-activated, it wouldn’t be able to spread.

The other main approach is to find a way to reactivate the HIV that’s hiding and take care of it, either with drugs or with the immune system, something scientists are calling the shock and kill strategy. At the very least, researchers are hoping to develop these methods into functional cures. But if they got every last virus, they could also be sterilizing cures.

The ultimate goal would be to eradicate HIV completely. But after more than 3 decades of trying, we still don’t have a vaccine. There are some promising leads, but it’s been difficult because the virus mutates so rapidly, and it’s hard to make one vaccine work against all the slightly different viruses out there.

So, we’ve come a long way, but there’s plenty of work left to do. Thanks for watching this episode of SciShow. It’s actually part of a mini-series.

If you’re interested in the story of how we discovered HIV in the first place, you can check out the first in the mini-series if you haven’t seen it yet. And for more videos on the most fascinating science stories out there, you can go to youtube.com/scishow and subscribe.