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 () and Michael Roche
Additional contact information
Paula M. Cevaal: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Stanislav Kan: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Bridget M. Fisher: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Michael A. Moso: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Abigail Tan: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Haiyin Liu: Monash University
Abdalla Ali: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Kiho Tanaka: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Rory A. Shepherd: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Youry Kim: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Jesslyn Ong: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Denzil L. Furtado: The University of Melbourne
Marvin Holz: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Damian F. J. Purcell: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Joshua M. L. Casan: Peter MacCallum Cancer Centre
Thomas Payne: Monash University
Wei Zhao: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Mohamed Fareh: Peter MacCallum Cancer Centre
James H. McMahon: Alfred Hospital and Monash University
Steven G. Deeks: San Francisco
Rebecca Hoh: San Francisco
Sushama Telwatte: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Colin W. Pouton: Monash University
Angus P. R. Johnston: Monash University
Frank Caruso: The University of Melbourne
Jori Symons: University Medical Center
Sharon R. Lewin: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity
Michael Roche: The University of Melbourne at The Peter Doherty Institute for Infection and Immunity

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60001-2

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