HIV cure research has come a long way over recent years and while scientists have not yet unlocked the secret to killing HIV hiding in the DNA of our immune cells as the latent HIV reservoir, there is much to be excited about in 2024. In my role as communications and engagement coordinator for Positive Women Victoria (PWV), I host a series of HIV health and wellbeing webinars and Melbourne-based HIV cure researcher Dr Jillian Lau was the special guest on our latest webinar HIV Cure Research in 2024.
As a woman living with HIV for 28 years, I follow HIV cure research very closely. Like most people living with HIV, I too feel ‘it’s time’. And after speaking with Dr Jillian Lau one of the few HIV researchers who can explain ‘in understandable terms’ the science behind HIV cure research, I am happy to report that there is much to be excited about as we move into 2024, which is also the year of AIDS2024, the 25th International AIDS conference hosted by the International AIDS Society and held in Munich, Germany in July.
There are four key HIV cure research strategies that scientists are working on in 2024. These include:
- Shock and kill strategy using cancer drugs such as venetoclax
- CRISPR-Cas9 gene editing
- Broadly neutralizing antibodies as a functional cure
- Immunotherapy to boost immune response to kill HIV
The latent HIV reservoir and why scientists can’t cure HIV just yet.
Before explaining the latest HIV cure science, Jillian advises that we need to take a step back to understand why scientists can’t cure HIV ‘at the moment’ and what is really going on deep inside our immune cells where HIV lies dormant in hiding.
“People with HIV can take a tablet every day or even injectable therapy every two months and the virus remains suppressed and undetectable. But we can’t eliminate HIV from the body because of this concept of the latent HIV reservoir,’ Jillian says.
Without antiretrovirals (ARVs), HIV invades immune cells called CD4 T-cells and makes copies of itself to infect other CD4 T-cells, killing the infected T cells in the process. ‘When a T cell is infected with HIV, HIV DNA binds to human DNA and this process can’t be undone. This is known as latent infection. ARVs prevent HIV from infecting new T cells by interrupting various stages of the virus life cycle, but even on treatment, these latently infected cells persist. This is known as the latent HIV reservoir. These T cells can’t be detected or cleared by our immune systems because they’re not creating new viral particles. These cells are also long lived. And this latent HIV reservoir is the main barrier to achieving a cure for HIV.
Six people cured of HIV from a stem cell transplant
To begin our conversation, I was curious about how six people have been cured of HIV from a stem cell transplant. They all had blood cancer, and had a bone marrow or stem cell transplant from a matching donor who was one of those rare individuals naturally resistant to HIV. While this treatment is expensive and risky, I asked Jillian if any ideas had emerged from this area that may lead to a cure.
‘After receiving a stem cell transplant and having chemotherapy, these six people then started with a whole new immune system that was naturally resistant to HIV, which is a really important concept in gene editing therapy,’ Jillian says.
So theoretically, we can cure HIV but stem cell transplants are a very specific, quite dangerous procedure, which is not scalable to people living with HIV around the world.
Let us move on to what 2024 holds for advances in HIV cure research in 2024.
Shock and kill using the cancer drug venetoclax
One of the earliest and still most well studied strategies to cure HIV is the ‘shock and kill’ strategy. Jillian explains the concept of Latent Reversing Agents or LRAs which work by shocking the latent or sleeping HIV out of its quiet state.
‘There’s been a lot of talk about shock and kill and the terminology that we use, which is a bit aggressive as we don’t want to kill the cells. We just want to eliminate cells that have HIV infection in them and keep the healthy cells and the uninfected cells,’ Jillian says.
HIV cure science has discovered a number of LRAs, which are often drugs used in cancer treatment, that can stimulate, or reactivate latent HIV, but scientists continue to struggle in eliminating the HIV cells once woken up.
‘We haven’t got the ‘kill’ part worked out yet,’ Jillian says. ‘We can see an increase in some of the viral particles in the blood when we measure it as part of these trials, but we’re not seeing a reduction in the reservoir, or the ‘kill’ part of shock and kill’
Jillian says scientists globally are looking at a more targeted latency reversal therapy and more specific cell death without causing harm to other healthy cells.
And one of the recently studied LRAs is the cancer drug venetoclax, which scientists have found success in the ‘kill’ part of ‘shock and kill’.
‘Cancerous cells have an ability to survive beyond normal cell lifetimes. This allows them to grow and mutate. Venetoclax is an apoptosis stimulating drug. Apoptosis is the process which guides cell death, and all cells eventually die like when our hair falls out. This is a normal part of life. Venetoclax, a cancer drug used in leukaemia, has been found to enhance the kill part of shock and kill in early HIV cure studies, and is now moving into clinical trials in humans.
A clinical trial called AMBER is a collaboration between scientists in Denmark and Melbourne, which uses venetoclax, and will start in 2025 in Melbourne. If you live in Victoria, you can register your interest by joining the trial at the Victorian Volunteer HIV Cure database.
Jillian explains that the AMBER trial with venetoclax is taken as a tablet in a much smaller dose as would be used to treat cancer.
‘AMBER does involve a treatment interruption, which means stopping your HIV treatment during the trial, but people are closely monitored. So that’s something to consider for those who might be interested in the study.’
Jill also explains that it takes a long time to get a trial like AMBER to a clinical human trial as it must go through lab trials to be proven to be safe for people first and foremost. The pre-clinical studies in venetoclax were performed in Melbourne, with donated blood samples from people living with HIV from Melbourne.
How is the latent HIV reservoir measured?
With venetoclax sounding like an exciting development in ‘killing’ the latent reservoir, it made me curious as to how do scientists measure the reservoir. How do they know how much of those latent cells have been ‘shocked’ awake and how many have been ‘killed’. This was of particular interest to me because by all accounts I have a pretty huge latent HIV reservoir having lived with HIV for 28 years and developed AIDS, when the virus ran rampant, in the early days before 1996 when effective HIV treatments were discovered.
But in comparison, someone who recently contracted HIV, and was diagnosed early, they have a very, very small HIV reservoir. So how does two different levels of latent cells in two different people, one with a large reservoir and one with a small reservoir, impact on the HIV cure trial results?
Jillian explains a challenging philosophical question amongst HIV cure scientists (when they are not peering down their microscopes).
‘Do we only target people with small reservoirs because they have a smaller threshold to start with, and therefore have a higher likelihood of cure or should everyone, because a cure for HIV needs to reach everyone living with HIV.’
‘I personally think we should not exclude people like yourself who’ve had HIV for a long time and have a larger reservoir. If we want a cure, it has to be for everyone. We can’t just have people who have small reservoirs who may have had a diagnosis within three months of infection, for example. But the counter argument to that is, this science is at the very early stage, we need to find some kind of signal, we need to see if something works. And if it does, we can then include the broader population.
Jillian adds that measuring the latent HIV reservoir is an area of HIV cure research that is advancing rapidly and there are likely to be a number of exciting research presentations at AIDS2024 about new technique to measure and characterise the reservoir.
‘We’ve learned recently that using HIV DNA as a measure of the reservoir grossly overestimates it’s size. We now know that a lot of HIV DNA is not virus that’s able to replicate and infect cells when it wakes up. The virus is “defective”. We now have new tests that are more specific to measure viral DNA, and tell us is it is “intact” or “defective”.
CRISPR-Cas9 gene editing
If you spend a bit of time reading HIV cure research, CRISPR is the latest buzzword but I’m not convinced as it is both expensive, and complicated to understand for the non-scientist like myself. I asked Jillian to please explain… in simple terms.
‘CRISPR-Cas9 gene editing is technology that is able to precisely cut sections of DNA to serve a specific purpose. It could try to provide protection against HIV for example, in the same way that the stem cell transplant worked on the six people who had blood cancer were cured of HIV. But there is a concern that if we snip the DNA here and there, will this have a flow on effect and 5, 10, 15 or 20 years time. Could snipping out this gene, which might protect you from HIV now, could it then increase someone’s risk of cancer or dementia many years in the future? And that’s why we need very careful research into this area, and close and prolonged follow up of people in clinical trials of gene therapy.
One issue is how do we deliver gene editing therapy? You can do something similar to a stem cell transplant, where you extract a bunch of white cells, which include CD4 T cells which HIV infects, gene edit them to for example be resistant to HIV, then insert them back into the body. But the problem is how to take out enough cells to gene edit and studies performed previously haven’t been able to effectively gene edit enough cells to have an effect. The other way is to do gene editing within the body, with technologies such as CRISPR-Cas9. A person gets an infusion of an agent that has gene editing capabilities that can cut and edit our DNA. CRISPR can target and cut out a gene.
However, CRISPR-Cas9 is already being used and is FDA approved in the United States for sickle cell anaemia, which affects red blood cells, but it is an expensive treatment leaving CRISPR a long way from being a practical cure for the 40 million people living with HIV globally.
‘CRISPR-Cas9 can cure sickle cell anaemia as a one-shot gene treatment, but it costs US$2.2 million. And in a similar way to HIV, the burden of sickle cell anaemia is in Sub Saharan Africa so this treatment is not affordable for one person. But it does show proof of concept that gene editing does work. And a recent Dutch study using gene editing in a test tube model found that they could snip out the HIV that had integrated into human DNA quite effectively. But then they found all these extra deletions and missing things and mutations in the DNA that hadn’t happened because of CRISPR, but it happened because the body was trying to repair itself. So random deletions are a real concern. But while gene editing technology is really exciting, we’ve got a long way to go to make sure it’s safe and scalable, and affordable,’ explains Jillian.
Broadly neutralising antibodies as a functional cure
I first heard of long term injectable ARVs combined with broadly neutralising antibodies or bNABs at the HIV science conference in Brisbane in 2023. There was a lot of excitement around the early data presented from the RIO study from the UK. The term functional cure was being hotly debated especially as some people did not have viral rebound (when HIV becomes active again) for up to 72 weeks.
‘Broadly neutralising antibodies are probably one of the most promising interventions that we’re looking at with HIV cure research at the moment,’ Jillian says.
Scientists discovered broadly neutralising antibodies (bNABs) by studying people with HIV who can naturally control HIV to undetectable levels without taking HIV treatment. They are called elite controllers. Scientists found that some of these elite controllers had these antibodies that were able to neutralise a large number of different HIV strains. Scientists then found a way to make these bNABs from proteins in the lab and give them via an infusion to people with HIV.
Jillian explains in an early trial of bNAbs, which included nine people with HIV, they stopped taking their ARVs to see if the bNAbs stimulated the body’s immune system to control HIV without ARVs. ‘But only two out of nine people were able to control the virus for up to eight months, because bNAbs wash out of the body (after around two or three weeks). And people can also develop resistance to bNAbs the same way they can to HIV treatments. But more recently, in the RIO study from the UK, they’re looking at longer acting versions of bNAbs combined with the new long-acting injectable ARV lenacapavir, which is given as a six-monthly injection. Then the thought is that maybe with prolonged exposure to these antibodies, the body’s immune system is able to be stimulated a bit like a vaccine. But at the moment, I wouldn’t put it in the HIV cure space. As for a functional cure, we’re not quite there yet. All the studies that are currently running require a top up every six months. But it is something to watch and it will be interesting to see the results from the RIO study presented at AIDS2024. Some of these studies are also looking at bNAbs in prevention which is also very exciting,’ says Jillian.
Immunotherapy treatment for HIV cure
Immunotherapy in HIV cure research looks at how to stimulate our body’s own immune system to detect and clear HIV similar to the kill part of ‘shock and kill’ therapy. Immunotherapy is already used in cancer treatment including melanoma, skin cancer and lung cancer.
Jillian explains that there is currently a HIV cure trial in Melbourne using immunotherapy where people with HIV are given a very low single dose of an immunotherapy cancer drug called an immune checkpoint inhibitor.
‘Previous studies showed that it works to shock the latent HIV awake and, in some people, kills the activated virus so there is a reduction in the reservoir. Immunotherapy is an important strategy, and we have another immunotherapy HIV cure study starting at the end of 2024 in Melbourne called PEACH. So a lot is happening right here in Melbourne in HIV cure research,’ Jillian says.
Will we see a cure for HIV in five years?
For as long as I can remember, I’ve heard a cure for HIV is five years away. And that was 20 years ago!
However, HIV cure science has come a long way in just the past few years but it seems we still have a long way to go as Jillian explains.
‘I’ve been working in HIV cure research for just over five years now and I’ve learned to not use that terminology of a cure being five years away! I think it’s misleading because it gives potentially false hope. And then it just makes us researchers liars when it’s five years later, and a cure hasn’t come. So now I’m just highlighting that since I’ve started working in HIV cure research, the science has made exponential leaps and bounds in technologies such as gene editing and in bNABs. Suddenly, in the last two years, there’s been an explosion of very specific tests of how we measure the reservoir, which has previously been a major issue. So while it might not seem as evident to the everyday person, there’s all this background advances happening and I think we’re close. We just need a major breakthrough similar to what happened with hepatitis C. After years and years and decades of research, suddenly there was a breakthrough. And now there’s a cure for Hep C. I think it will be a similar process for HIV. We’re learning so much, but we’re not quite there yet. I can’t stress enough that we’re not close at the moment. But that doesn’t mean we shouldn’t keep trying and we shouldn’t have hope.
The HIV Cure website has regular updates in Australia and globally.
To register interest for HIV cure research activities, visit the Victorian Volunteer HIV Cure Database.
Published: January 2024