Published on 09/06/2025
Scientists have found a breakthrough in the search for a cure for Human Immunodeficiency Virus (HIV), after research uncovered a development “previously thought impossible”.
The virus’s ability to conceal itself inside certain white blood cells has been one of the main challenges for scientists looking for a cure. It means there is a reservoir of the HIV in the body, capable of reactivation, that neither the immune system nor drugs can tackle.
Now researchers from the Peter Doherty Institute for Infection and Immunity in Melbourne, have demonstrated a way to make the virus visible, paving the way to fully clear it from the body.
It is based on mRNA technology, which came to prominence during the Covid-19 pandemic when it was used in vaccines made by Moderna and Pfizer/BioNTech.
READ: FULL RESEARCH COPY
Efficient mRNA delivery to resting T cells to reverse HIV latency | Nature Communications
Globally, there are almost 40 million people living with HIV, who must take medication for the rest of their lives in order to suppress the virus and ensure they do not develop symptoms or transmit it. For many it remains deadly, with UNAids figures suggesting one person died of HIV every minute in 2023.
It was “previously thought impossible” to deliver mRNA to the type of white blood cell that is home to HIV, said Dr Paula Cevaal, research fellow at the Doherty Institute and co-first author of the study, because those cells did not take up the fat bubbles, or lipid nanoparticles (LNPs), used to carry it.
The team have developed a new type of LNP that those cells will accept, known as LNP X. She said: “Our hope is that this new nanoparticle design could be a new pathway to an HIV cure.”
When a colleague first presented test results at the lab’s weekly meeting, Cevaal said, they seemed too good to be true.
“We sent her back into the lab to repeat it, and she came back the next week with results that were equally good. So we had to believe it. And of course, since then, we’ve repeated it many, many, many more times.
“We were overwhelmed by how [much of a] night and day difference it was – from not working before, and then all of a sudden it was working. And all of us were just sitting gasping like, ‘wow’.”
Further research will be needed to determine whether revealing the virus is enough to allow the body’s immune system to deal with it, or whether the technology will need to be combined with other therapies to eliminate HIV from the body.
The study is laboratory based and was carried out in cells donated by HIV patients. The path to using the technology as part of a cure for patients is long, and would require successful tests in animals followed by safety trials in humans, likely to take years, before efficacy trials could even begin.
“In the field of biomedicine, many things eventually don’t make it into the clinic – that is the unfortunate truth; I don’t want to paint a prettier picture than what is the reality,” stressed Cevaal. “But in terms of specifically the field of HIV cure, we have never seen anything close to as good as what we are seeing, in terms of how well we are able to reveal this virus.
“So from that point of view, we’re very hopeful that we are also able to see this type of response in an animal, and that we could eventually do this in humans.”
Dr Michael Roche of the University of Melbourne and co-senior author of the research, said the discovery could have broader implications beyond HIV, with the relevant white blood cells also involved in other diseases including cancers.
Dr Jonathan Stoye, a retrovirologist and emeritus scientist at the Francis Crick Institute, who was not involved in the study, said the approach taken by the Melbourne team appeared be a major advance on existing strategies to force the virus out of hiding, but further studies would be needed to determine how best to kill it after that.
He added: “Ultimately, one big unknown remains. Do you need to eliminate the entire reservoir for success or just the major part? If just 10% of the latent reservoir survives will that be sufficient to seed new infection? Only time will tell.
“However, that does not detract from the significance of the current study, which represents a major potential advance in delivery of mRNA for therapeutic purposes to blood cells.”
Prof Tomáš Hanke of the Jenner Institute, University of Oxford, disputed the idea that getting RNA into white blood cells had been a significant challenge. He said the hope that all cells in the body where HIV was hiding could be reached in this way was “merely a dream”.
mRNA Delivery Targets Resting T Cells In HIV
A recent study published in Nature Communications introduces a groundbreaking approach to HIV treatment by effectively delivering mRNA to resting CD4+ T cells, a significant challenge in the field. The researchers, from the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, developed a lipid nanoparticle (LNP) formulation, termed LNP X, capable of transfecting these hard-to-reach cells without inducing toxicity or activation.
“Our hope is that this new nanoparticle design could be a new pathway to an HIV cure,” said Dr. Paula Cevaal, a research fellow at the Doherty Institute and co-first author of the study.
The researchers identified a novel LNP formulation with the unique capability to transfect CD4+ T cells without the need for pre-stimulation. Using this formulation, called LNP X, they encapsulated two mRNA-based latency-reversing agents (LRAs), which demonstrated efficient activation of HIV transcription in CD4+ T cells from people living with HIV on antiretroviral therapy ex vivo.
LNP X was engineered by replacing the conventional ionizable lipid DLin-MC3-DMA with SM-102 and incorporating β-sitosterol, enhancing its ability to deliver mRNA into the cytosol of resting T cells. This formulation achieved up to 76% transfection efficiency in non-stimulated CD4+ T cells, a notable improvement over existing methods.
The study demonstrated that LNP X could deliver mRNA encoding the HIV Tat protein, a potent activator of HIV transcription. In ex vivo experiments using CD4+ T cells from individuals on antiretroviral therapy, Tat-LNP X significantly increased HIV RNA transcription without causing cellular activation or toxicity. This suggests that LNP X can reverse HIV latency effectively while maintaining cell viability.
Furthermore, LNP X was used to co-deliver components of the CRISPR activation system, including dCas9-VP64 mRNA, MS2-p65-HSF1 mRNA, and guide RNAs targeting the HIV long terminal repeat region. This approach successfully activated HIV transcription in resting CD4+ T cells, highlighting the versatility of LNP X in delivering complex RNA-based therapeutics.
To the researchers’ knowledge, this is the first demonstration of successful, non-toxic in vitro transfection of primary T cells without the need for T cell pre-stimulation, a condition previously believed to be essential for efficient LNP transfection. These data suggest that the superior potency of LNP X results from increased cellular association and enhanced efficiency of mRNA translation after cytosolic delivery, which contrasts with earlier hypotheses that attributed improved performance to enhanced endosomal escape mediated by β-sitosterol.
“In the field of biomedicine, many things eventually don’t make it into the clinic—that is the unfortunate truth; I don’t want to paint a prettier picture than what is the reality,” Cevaal shared with The Guardian. “But in terms of specifically the field of HIV cure, we have never seen anything close to as good as what we are seeing, in terms of how well we are able to reveal this virus.”
