By Heather Ellis, originally published in NAPWHA’s Positive Living magazine
With a HIV cure more elusive than ever, Heather Ellis who attended AIDS2024 virtually, discovered HIV scientists have turned their attention to innovative ‘nano-formulation’ strategies to out-smart HIV in hiding and are researching more effective treatments that will ‘hopefully’ reduce the HIV reservoir and therefore low level inflammation.
Hosted by IAS (International AIDS Society), AIDS2024, the 25th International AIDS Conference was held in Munich, Germany from 22 to 26 July. Held every two years in person and virtually, this is the world’s largest HIV conference bringing together scientists, clinicians, policy makers and people living with HIV to discuss and learn about the latest developments in HIV science and advocacy. The theme for AIDS2024 was: ‘Put People First’.
The 7th Person Cured of HIV
One of the most exciting conference stories was the 7th person cured of HIV. Known as “The Next Berlin Patient” after the city where he had the procedure, this person, who remains anonymous, received a stem cell transplant from a donor who has a genetic mutation of the CCR5 receptor, meaning HIV can’t attack their immune cells.
Timothy Ray Brown, the first Berlin Patient, received two copies of the CCR5 mutation as did most of the other people cured. The Next Berlin Patient’s donor only had one. It was previously thought that two copies were needed to block HIV.
At a pre-conference on HIV cure, we met three people who had been cured, including: The Dusseldorf Patient, Marc Franke; The London Patient, Adam Castillejo; and Paul Edmonds, The City of Hope Patient. Marc, who is 55, shared his experience from 11 years ago when he was diagnosed with blood cancer, had intensive chemotherapy and then received a stem cell transplant from a donor with two copies of the CCR5 mutation. Marc was the second person cured of HIV with a stem cell transplant.
The 6th person, The Geneva Patient, received stem cells from a donor with no CCR5 mutation. The results were presented at the IAS HIV Science Conference in Brisbane last year and scientists were very excited indeed. These latest two patients cured of HIV show that it’s not just about the CCR5 mutation.
Some scientists have theorised that the chemotherapy first washes most of the HIV out of the body and then with new immune cells, the body can beat what little HIV remains.
Because it is so invasive, intensive chemotherapy and a stem cell transplant is reserved only for those with terminal blood cancer.
Marc Franke shared how he endured four years of immunosuppressant drugs plus a cocktail of other treatments to manage side effects. As a result, he had liver inflammation, contracted a herpes infection that went to his brain, and lost bone density that led to a broken hip. In a recent publication describing 30 people with HIV with cancer in Europe who underwent this treatment, half died and only seven were cured. So, while stem cell transplants are not a universal cure, the latest two people cured does give scientists hope as they try to understand: ‘If it is not the CCR5 receptor, then what is it?’
Cracking the Code of the HIV Reservoir
AIDS2024 will be remember as the HIV Reservoir conference as there was certainly a focus. Scientists know that no cure will be found without cracking the code of the HIV reservoir. This latent HIV hides in the DNA of our long-lived immune cells where it can not be reached by HIV treatments. Some of this latent virus is intact and even with treatments continues to produce HIV particles called viral RNA which causes low level inflammation. If HIV treatment is stopped, the HIV reservoir is suddenly woken up as nothing is suppressing it. HIV begins to replica and destroys our immune system leading to AIDS.
The Last Gift Study and the HIV Reservoir
Eleven people with HIV who donated their bodies to HIV science for The Last Gift Study were honoured at AIDS2024, and for what their gift revealed about levels of the HIV reservoir in tissues and organs. In order to get the most accurate measurement before cells decayed, autopsies were done within six hours of their death. The results about the invasiveness of the HIV reservoir was far worse than expected. While scientists have known the HIV reservoir hides in immune cell sites, such as the gut and the lymph nodes, and to a lesser extent the brain, the autopsies revealed that the HIV reservoir is found in every tissue and organ. This means clearing the body of the HIV reservoir suddenly got far more complicated and any HIV cure strategy is likely to be on a far more distant horizon. However, scientists also now have far more accurate data from deep tissue samples from the 11 Last Gift donors and as a result a better understanding of what they are dealing with in this war on the HIV reservoir for both cure and for more effective HIV treatments.
Using bNAbs to clear the HIV reservoir hiding in the brain
Firstly, let’s take a moment to understand bNAbs or broadly neurtslising anti-bodies. Scientists discovered bNABs about 10 years ago by studying ‘elite controllers’: people with HIV ‘ who can naturally control HIV to undetectable levels without taking HIV treatment. They 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 in clinical trials. The research continues and so far has not provided the potential cure results that scientists had hoped.
While there was much excitement around bNAbs at the HIV science conference in Brisbane in 2023, at AIDS2024 this hype seemed to have died down. However, there was one session that used an innovative approach with bNAbs to reach the HIV reservoir hiding in the brain. There is no point clearing the body of the HIV reservoir, if it is not also cleared from the brain no matter how small it might be. It just takes one intact viral particle for HIV to replicate so for any cure to work, it must cross the blood brain barrier. Promising findings were presented that tricked the brain into letting the bNAbs in. Knowing the brain loves glucose (sugar), which it uses for energy, scientists used bio-engineering to sugar-coat bNAbs. But normal bNAbs arn’t tiny enough to cross the blood brain barrier so these were also engineered as nano-capsules using antibodies taken from llamas. Animals from the camel family, which includes llamas and alpacas, have much smaller anti-bodies than humans. These sugar-coated nano-bNAbs were injected into four baby monkeys infected with a monkey-form of HIV. Once inside the brain, the coating dissolves and the bNAbs attacked the HIV reservoir. Three of the four monkeys achieved full suppression of the HIV reservoir in their brains. But monkeys are a lot different from humans and this research is still in its infancy.
Attacking the HIV reservoir with nano-packaged HIV drugs
We know how effective existing HIV drugs are in suppressing HIV so scientists presented findings on how they have engineered existing HIV drugs into nano-formulations that will reduce the HIV reservoir. A trial using the HIV drugs: FTC/TDF and DTG packaged into nano-formulations and injected into mice infected with HIV, showed a significant decrease in the P24 antigen. This is a viral protein produced by HIV, and any decrease signifies a decrease in the reservoir. While scientists weren’t excited about this as a possible cure, these nano-packaged HIV drugs could pave the way for more effective long-acting treatments that may reduce the HIV reservoir and therefore reduce low level inflammation.
HIV reservoir in the Gut and the role of GP120
In this session, appropriately titled ‘The Devil Wears GP120’, researchers presented findings on the role of GP120, a protein that HIV infected cells shed. This GP120 may act as a toxin and could be a key driver of low level inflammation even when on HIV treatment and with an undetectable viral load. The area where HIV ‘the devil’ is sheding GP120 the most is in the gut as this is the largest site of the HIV reservoir. When we lived in caves (our bodies have not really changed since), and ingested all sorts of crap as we chewed on mammoth bones, we also ingested pathogens so it makes sense that the body’s immune system (CD4 T-Cells), is concentrated in the gut, which starts in our mouth all the way to our anus. Unfortunately, the gut never fully recovers from the initial HIV infection when HIV destroys our CD4 T-Cells in the gut and weakens its permeability. This weakened gut barrier allows bacteria particles to penetrate into our blood stream, especially from the small intestine, which then causes persistent low level inflammation.
The Re-Start Trial in Canada in partnership with ViiV Healthcare is looking at using the existing HIV drug Fostemsavir to detoxify the body of GP120 to will help reduce this ongoing low level inflammation. Fostemsavir is an HIV attachment inhibitor which binds to and inhibits the activity of GP120 protein. It was FDA approved in 2020 for people with multi-drug resistance. In this presentation, researchers advised that the addition of fostemsavir to an existing HIV drug regime may lead to decreased inflammation, improve immune function and decrease heart disease risk. Previous studies show that Fostemsavir helps increase CD4 T-cell count. But like all medications, there are side effects and some people taking fostemsavir develop liver problems especially those with a history of hepatitis infection. Findings from the trail are likely to be presented at the IAS HIV Science conference in Rwanda in 2025.
Maybe the answer lies in CD8 T-cells or Natural Killer cells
Scientists are looking deeper into CD8 T-cells or Natural Killer cells, the ‘big guns’ of our immune system, to find out why these are more robust in elite controllers and not in the rest of us. The theory is, if science can find ways to reverse CD8 T-cell dysfunction then further research may find a way to use these Natural Killer cells to wipe out the HIV reservoir when HIV drugs are stopped and active virus starts replicating. Scientists in this presentation showed how they are looking at Interluken-15, a protein, to serve as a growth factor for CD8 T-cells. Lab-manufactured Interluken-15 was used as a possible HIV treatment back in the 1980s and 1990s before effective HIV treatments were discovered. However Interluken-15 has some nasty side-effects including renal failure and seizures. But its early days and maybe further research will discover ways around these side-effects to use Interluken-15 to boost our Natural Killer cells and gun down HIV as it emerges from hiding.
Is this the end of CRISPR-Cas gene-editing?
Findings on the first human safety trial using gene-editing was presented at AIDS2024. Six men with HIV had an infusion where CRISPR-Cas gene-editing targets HIV DNA and cuts it out. While there were no adverse effects, HIV rebound occurred in five of men after two weeks. The six is likely to have been a post-treatment controller, which is where some people (4% to 16%), with HIV after stopping HIV drugs, naturally control HIV replication. In this session, there was a real sense of doom and I got the feeling some scientists have given up on gene-editing due to so many negative variables. These include the possibility of unintended large chromosomal deletions which could mean the loss of tumour suppressor genes. Plus gene-editing must get 100% of the HIV DNA and this takes multiply editing infusions otherwise viral rebound will occur. Then patients need to be followed up for 15 years to monitor any long-term consequences. And the question was rightly asked: ‘who pays for this’. Gene-editing is already successfully used to treat Sickle Cell Disease at a cost of US$2.2 million per patient so it’s hardly scalable for the 38 million people globally living with HIV. However, scientists have not given up and as long as they continue to receive the ‘eye watering’ amounts of research funding, the CRISPR-Cas gene-editing show will go on.
Prof. Beatriz Grinsztein from Brazil takes over as IAS President
At the end of every AIDS conference, a new International AIDS Society president takes on the role. Melbourne’s Prof. Sharon Lewin stepped down as IAS president at the end of AIDS2024 handing over to Prof. Beatriz Grinsztein from Brazil. Prof Grinsztein, an infectious disease physician-researcher, will lead the IAS including its HIV Science Conference in Rwanda in 2025 and AIDS2026, which will be hosted in Latin America. However, the location has not yet been announced; however Brazil is rumoured as the hot favourite.
Links
HIV Cure Australia website for latest updates on HIV cure research in Australia and around the world
AIDS2024 conference session recordings opens to public on 26 September 2024
Learn about the HIV reservoir in this webinar series: Where Do HIV Reservoirs Reside?
Heather Ellis bio
Heather Ellis has lived with HIV since 1995. She is an HIV advocate, published author, journalist and motorcycle adventurer. Heather’s two books are the best-selling travel memoirs: Ubuntu: One Woman’s Motorcycle Odyssey Across Africa (Black Inc., 2016) and Timeless On The Silk Road: An Odyssey From London to Hanoi (Phonte, 2019). Heather is the communications and engagement coordinator for Positive Women Victoria based in Melbourne, a member of the National Network of Women Living With HIV Australia; and is a member of the community advisory board for the Melbourne HIV Cure Consortium. Read more about Heather at: www.heather-ellis.com
