Has mRNA delivered a breakthrough in quest for HIV cure?

Using mRNA to stop HIV from hiding away in white blood cells could be the key to developing a way to eradicate the infection, rather than simply managing viral levels in the body.

The tantalising development has been reported by researchers at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, who have used mRNA to force HIV to be mobilised from the reservoir of latent virus integrated into resting CD4-positive T lymphocytes in lab studies.

Viruses that remain in that latent state cannot be targeted using standard antiretroviral therapy (ART) for HIV, so while treatment can suppress it to almost undetectable levels, the dormant viruses can re-emerge if treatment is interrupted.

Exposing that reservoir could, in theory at least, render the viruses vulnerable to ART and allow the infection to be eradicated.

The Doherty Institute researchers have worked out a way to deliver mRNA sequences that force HIV out of hiding to this cell population, something that was previously thought to be impossible because CD4+ T cells lack the cellular mechanism needed to take up the lipid nanoparticles (LNPs) that are usually used to deliver large molecules like RNA.

Research fellow Dr Paula Cevaal – the lead author of a paper on the work published in Nature Communications – told The Guardian that the team had solved that challenge by designing a new type of LNP – dubbed LNP X – that can be taken by resting CD4+ cells and allow mRNA-based latency-reversing agents (LRAs) to be delivered.

While other types of LRAs, including oral HDAC inhibitors, have been tested in trials, none have been able to reduce the size of the HIV reservoir, according to the researchers. The mRNAs offer greater potency, switching off the genetic sequences that block viral replication, and don't seem to cause any toxicity to the host cells, according to the paper.

According to Cevaal, the initial data with the LNP X approach were so good that the team was unconvinced by the results and repeated the experiments again and again.

The approach "could be a new pathway to an HIV cure," she said, whilst acknowledging there is still a long way to go before human clinical testing is an option.

"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," she added. "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."

The work also raises the possibility of using LNP X to target T cell populations associated with other diseases with mRNA-based therapeutics.

Image by Darwin Laganzon from Pixabay