Efficient mRNA delivery to resting T cells to reverse HIV latency PMID: 40442114

ADC Targets in Oncology

2026-04-10

Efficient mRNA delivery to resting T cells to reverse HIV latency

Nat Commun. 2025 May 29;16(1):4979. doi: 10.1038/s41467-025-60001-2.

Paula M Cevaal ^# ¹ , Stanislav Kan ^# ¹ , Bridget M Fisher ^# ¹ , Michael A Moso ^# ¹ ² , Abigail Tan ¹ , Haiyin Liu ³ , Abdalla Ali ¹ , Kiho Tanaka ¹ , Rory A Shepherd ¹ , Youry Kim ¹ , Jesslyn Ong ¹ , Denzil L Furtado ⁴ , Marvin Holz ⁵ , Damian F J Purcell ⁵ , Joshua M L Casan ⁶ ⁷ , Thomas Payne ³ , Wei Zhao ¹ , Mohamed Fareh ⁶ ⁷ , James H McMahon ⁸ , Steven G Deeks ⁹ , Rebecca Hoh ⁹ , Sushama Telwatte ¹ , Colin W Pouton ³ , Angus P R Johnston ³ , Frank Caruso ⁴ , Jori Symons ¹⁰ , Sharon R Lewin ¹¹ ¹² ¹³ , Michael Roche ¹

Affiliations

1. Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
2. Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
3. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
4. Department of Chemical Engineering, The University of Melbourne, Parkville, VIC, Australia.
5. Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
6. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
7. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
8. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia.
9. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
10. Translational Virology, Department of Medical Microbiology, University Medical Center, Utrecht, the Netherlands.
11. Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. [email protected].
12. Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. [email protected].
13. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia. [email protected].
# Contributed equally.

Abstract

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.