Researchers at the Peter Doherty Institute for Infection and Immunity in Melbourne have achieved a significant breakthrough in HIV cure research by developing a method to force the virus out of its cellular hiding places using mRNA technology. The discovery, published in Nature Communications, represents a major advance in addressing one of the most persistent challenges in HIV treatment.
The virus's ability to conceal itself inside certain white blood cells has long been one of the main obstacles for scientists seeking a cure. This creates a reservoir of HIV in the body that remains capable of reactivation, which neither the immune system nor current medications can effectively tackle. Nearly 40 million people worldwide live with HIV and must take medication for life to suppress the virus, with UNAIDS data showing one person died from HIV every minute in 2023.
Revolutionary mRNA Delivery System
The Melbourne team's approach builds on mRNA technology that gained prominence during the COVID-19 pandemic. For the first time, researchers have demonstrated that mRNA can be delivered into cells where HIV is hiding by encasing it in specially formulated lipid nanoparticles (LNPs). Once delivered, the mRNA instructs the cells to reveal the virus.
"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. The challenge existed because these cells did not take up the fat bubbles or lipid nanoparticles traditionally used to carry mRNA.
The breakthrough came with the development of a new type of LNP, designated LNP X, that these previously inaccessible cells will accept. "Our hope is that this new nanoparticle design could be a new pathway to an HIV cure," Cevaal explained.
Overwhelming Research Results
The initial test results were so promising that researchers initially questioned their validity. When a colleague first presented the findings at the laboratory's weekly meeting, Cevaal recalled, "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."
The team has since replicated the results numerous 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'," Cevaal described.
Dr. Michael Roche of the University of Melbourne and co-senior author of the research noted that the discovery could have broader implications beyond HIV, as the relevant white blood cells are also involved in other diseases including cancers.
Path to Clinical Application
The research is currently laboratory-based and was conducted using cells donated by HIV patients. The path to clinical application remains long and complex, requiring successful animal testing followed by safety trials in humans before efficacy studies could begin – a process likely to take years.
"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 cautioned. However, she expressed optimism about the specific field of HIV cure research: "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."
Further research will be needed to determine whether revealing the virus is sufficient for the body's immune system to eliminate it, or whether the technology will need to be combined with other therapies to fully clear HIV from the body.
Expert Perspectives
Dr. Jonathan Stoye, a retrovirologist and emeritus scientist at the Francis Crick Institute who was not involved in the study, described the Melbourne team's approach as "a major advance on existing strategies to force the virus out of hiding." However, he noted that further studies would be needed to determine the best methods for eliminating the virus once it's revealed.
Stoye highlighted a critical unknown: "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."
Despite these uncertainties, Stoye emphasized the significance of the current study, stating it "represents a major potential advance in delivery of mRNA for therapeutic purposes to blood cells."
The research team remains hopeful that they will be able to demonstrate similar responses in animal models and eventually translate the technology to human applications, potentially offering new hope for the millions of people living with HIV worldwide.
