Efficient mRNA delivery to resting T cells to reverse HIV latency
- Paula M. Cevaal
- Stanislav Kan
- Bridget M. Fisher
- Michael A. Moso
- Abigail Tan
- Haiyin Liu
- Abdalla Ali
- Kiho Tanaka
- Rory A. Shepherd
- Youry Kim
- Jesslyn Ong
- Denzil L. Furtado
- Marvin Holz
- Damian F. J. Purcell
- Joshua M. L. Casan
- Thomas Payne
- Wei Zhao
- Mohamed Fareh
- James H. McMahon
- Steven G. Deeks
- Rebecca Hoh
- Sushama Telwatte
- Colin W. Pouton
- Angus P. R. Johnston
- Frank Caruso
- Jori Symons
- Sharon R. Lewin
- Michael Roche
2025-05-29
A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4 + T cells that remain in a transcriptionally silent, latent state. One strategy to eradicate latent HIV is to activate viral transcription, followed by elimination of infected cells through virus-mediated cytotoxicity or immune-mediated clearance. We hypothesised that mRNA-lipid nanoparticle (LNP) technology would provide an opportunity to deliver mRNA encoding proteins able to reverse HIV latency in resting CD4 + T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4 + T cells in the absence of cellular toxicity or activation. Encapsulating an mRNA encoding the HIV Tat protein, an activator of HIV transcription, LNP X enhances HIV transcription in ex vivo CD4 + T cells from people living with HIV. LNP X further enables the delivery of clustered regularly interspaced short palindromic repeats (CRISPR) activation machinery to modulate both viral and host gene transcription. These findings offer potential for the development of a range of nucleic acid-based T cell therapeutics.