If you’re looking for the virus that’s challenged scientists the most in the last 40 years. HIV is there!! For a while, every time we develop a new treatment for it, the virus would just mutate (Mutate meaning, the feature of viruses to perform a viral genetic change in their own genome). So the drug didn’t work anymore. 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. 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 be able to manage and control the disease.
So what’s the relief?
Today with the recommended treatments someone who’s HIV positive is expected to live nearly as long as someone who’s uninfected. Researchers are working on all kinds of new ideas to kick even more virus 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. What most doctors could do was to treat the infections patients developed. This is because the virus had killed off so many T-cells that they were left with basically no immune system.
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History of drugs used to treat HIV/AIDS
Sermon
One of the very first drugs that showed promise against the HIV virus itself was Sermon. Sermon 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. It actually made them sicker because the drug was pretty toxic.
How AZT evolved, its side effects and downfall?
Labs then started to test old compounds for anything that might work. 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. 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. Doctor’s eventually realized that a lower dose of AZT could get rid of a lot of those problems. The drug had an even bigger pitfall, it only worked for a limited time but after a while, the levels of virus and the person’s blood started to tick back up. It had mutated in a way that meant AZT couldn’t block reverse transcriptase anymore.
Why is HIV incurable? How it produces resistance to drugs? How scientists are fighting this problem?
That’s the major challenge in 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. 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. Then came this drug, Protease inhibitor which was approved in December of 1995. Protease are enzymes that cut proteins into smaller pieces. 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 too had some pretty severe side effects and only worked until the virus mutated.
In the form of Protease Inhibitors now the doctors had drugs that targeted to different parts of the HIV life cycle. This also meant that they could combine them making it much harder for the virus to mutate to escape both drugs that changed everything.
How antiretroviral therapy or ART evolved?
In 1996 doctors started giving patients these combination made of at least two and soon three or four drugs. They called it highly active antiretroviral therapy. It worked so much better than the individual antiretroviral, 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 combo many with fewer and less severe side effects than before. This is the breakthrough that changed HIV infection from a death sentenced 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 and patients is often undetectable. ART not only 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 moral of the story is more people who can be put on ART, the better it is, not just for them but for everyone.
What is PREP? How it evolved?
Researchers have taken this idea a step further with what’s called pre-exposure prophylaxis or prep. Where people who are at higher 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. This is actually one of the biggest problems in the HIV world. Things like side-effects or trouble remembering when to take which pills. It sometimes makes 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. So 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 drugs 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.
Types of Potential cures for HIV/AIDS
There are two main types of potential cures
- Sterilizing cure
- Functional Cure
The sterilizing cure is what you would think of as a cure, that is total eradication from the body with absolutely no virus left.
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. It turns out a sterilizing cure is extremely difficult. In fact, it’s only happened for one person.
How did HIV Functional cure work?
A man named Timothy Brown aka the Berlin patient he was HIV positive and also had leukemia. Doctors have 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. 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 then transferred in those special bone marrow cells. 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 and chances of survival after bone marrow transplant is less. 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….
Why Functional cure for HIV is the only way?
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.
A functional cure is much more promising and researchers are looking at a bunch of different strategies. One thing that 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 of the antiretrovirals. The problem is HIV is very good at hiding. The virus stays hidden in cells called latent reservoir and it doesn’t try to replicate in those cells which means antiretrovirals have no effect. So the virus isn’t causing any harm it’s still there. and it could become reactivated 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 reactivated 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. After more than three 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.
