How is HIV treated

How do antiretroviral drugs work
08 December 2020

Interview with 

Ravi Gupta, University of Cambridge


CGI images of DNA double helix


When HIV was first discovered, bullish noises were made by researchers and politicians worldwide that there would be a vaccine before long. That hasn’t happened yet, and we’ll come to why later in the programme, but the development of drugs to control the infection certainly has been a success story and it’s been possible to convert what would have been a lethal infection into a treatable disease. These drugs are called antiretrovirals. So how do they work? Chris Smith spoke to Ravi Gupta, who specialises in HIV at the University of Cambridge

Ravi - So as my colleague Rowena mentioned, the virus is an unusual virus: a retrovirus. And that means that it comes in with a genetic code that's actually made up of RNA, and what it needs to do is make DNA. And so what it does is uses an enzyme called reverse transcriptase which converts that RNA to DNA; and this is a key enzyme without which the virus can't survive. And one of the main classes of drugs that we treat HIV with is a class called reverse transcriptase inhibitors, and these are drugs designed to block that enzyme. Now after the virus has made DNA versions of its genetic material, the HIV genetic code in fact becomes part of our own genetic code, in our white blood cells; and that's a process called integration. And that's another target of antiretroviral drugs. Once the virus has become part of your genetic material, it then undergoes what we call a reactivation event, where it starts generating copies of itself, essentially. Once that process has started, you get protein units, and they need to be chopped up into the relevant pieces in order for the virus to mature; so those proteins are generated as long chains, they need to be cleaved. That process is coordinated by an enzyme that HIV encodes, it's called protease. This causes those chopping up events in order to enable maturation of the virus. And that's a third, very potent class of drugs: labelled protease inhibitors. So those are three general drug pluses that have been used to treat HIV, that really follow the life cycle.

Chris - And we tend to use them in combination. It's not like if I had meningitis, and someone would give me the antibiotic best for treating that bacterium; when we treat HIV, we use combinations of these drugs all at once. That's called HAART, isn't it? Highly Active Antiretroviral Therapy. Why do we do that?

Ravi - Yes, this is a very, very important point, and it's one of the things that made HIV so hard to control for so long. Because this virus mutates so rapidly, as you mentioned earlier - and that's one of its survival strategies - it also generates large numbers of viruses very quickly. So you've got a huge number of virus replication events going on in the body at any one time. If you imagine a drug going in there, depending on how potent the drugs are, there will always be a few viruses that have got mutations that escape that drug; and therefore those viruses will survive and they'll carry on generating copies of themselves, and gradually that will take over the virus population. We try and get around that by using combinations of drugs, so that at any one time we can block almost all mutants that are generated, and therefore with combinations of drugs, the probability of a virus coming up with mutations to all two or three drugs is then diminishingly small. And that's what gives you the chance of long term suppression of HIV replication.

Chris - It's a bit like the Swiss cheese model, isn't it, where you've got holes in the Swiss cheese and you just put lots and lots of slices, and the holes don't line up; so the chance of a virus floating through all three slices is very slim indeed. Why though, if these drugs are so potent, and so effective, and people have unrecordable levels of virus in their body when they're on them... why are they not cured?

Ravi - This goes back to the idea of integration. Although we can reduce the numbers of new viruses coming out of cells, it's very difficult to destroy or remove those white blood cells that have been infected during the course of the infection, because of this integration event that I mentioned earlier. Now one of HIV's genius strokes, you might say, is it preferentially targets what we call memory CD4 cells; and these are white blood cells that offer us lifelong protection from infections that we encounter during our lifetimes. And so these white blood cells are there to protect us over many decades, and reactivate as soon as they see that pathogen again. And because HIV goes into these sorts of cells, this long lifespan enables HIV to essentially persist indefinitely.

Chris - But there have been cures - okay, two of them - haven't there. What's happened in those people who've been cured of HIV?

Ravi - The reason that cure has been made possible is really due to the fact that chemotherapeutic drugs have the ability to destroy these memory CD4 T cells that I've been talking about. And this knowledge of destruction of white blood cells is combined with another piece of knowledge that science brought us, which is that the protein CCR5 - which is essential for HIV to cause infection of cells in the first place, because it's a receptor on the surface of your cells - this protein is in fact absent in about 1% or less of Europeans. And if you have a dysfunctional or an absent CCR5, you're actually protected from actually being infected with HIV in the first place. And some doctors in Germany decided that they would aim to cure an individual, and the individual's now termed the Berlin patient, Timothy Ray Brown. They aimed to replace the blood system with a system that was resistant to infection with this CCR5 deletion; and combined with the chemotherapy, or the regimen to ablate or remove the white blood cells from the patient to allow the new blood cells to come in. And that that process probably destroyed a lot of the HIV, or if not all HIV infected cells; thereby allowing you to replace the blood system with a resistant one, and at the same time kill all the HIV infected cells in the body. And that's how we think the cure happened.


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