Efficient mRNA delivery to resting T cells to reverse HIV latency
A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4<sup>+</sup> 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<sup>+</sup> T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Kiho Tanaka
- Mohamed Fareh (ORCID: https://orcid.org/0000-0001-9551-8213)
- Frank S Caruso (ORCID: https://orcid.org/0000-0002-0197-497X)
- Wei Zhao (ORCID: https://orcid.org/0000-0003-4337-4064)
- Michael A. Moso (ORCID: https://orcid.org/0000-0001-7948-3380)
- Denzil Furtado (ORCID: https://orcid.org/0000-0001-6550-4232)
- Abigail Er Qi Tan
- Jesslyn Ong
- Ali Abdalla (ORCID: https://orcid.org/0000-0002-1444-2112)
- Rebecca Hoh (ORCID: https://orcid.org/0000-0001-5112-4220)
- Michael J. Roche (ORCID: https://orcid.org/0000-0003-1198-9654)
- Colin William Pouton (ORCID: https://orcid.org/0000-0003-0224-3308)
- Haiyin Liu (ORCID: https://orcid.org/0000-0003-3103-6949)
- Damian F. J. Purcell (ORCID: https://orcid.org/0000-0002-4485-1726)
- Benjamin D. Fisher
- Sushama Telwatte (ORCID: https://orcid.org/0000-0003-4086-5212)
- Paula M. Cevaal (ORCID: https://orcid.org/0000-0003-4473-7904)
- Youry Kim (ORCID: https://orcid.org/0000-0002-1216-4999)
- Sharon R. Lewin (ORCID: https://orcid.org/0000-0002-0330-8241)
- Steven G. Deeks (ORCID: https://orcid.org/0000-0001-6371-747X)
- Stanislav Kan
- Angus P. R. Johnston (ORCID: https://orcid.org/0000-0001-5611-4515)
- Mareike Holz
- Joshua M. L. Casan (ORCID: https://orcid.org/0000-0002-4322-8561)
- Thomas J. Payne (ORCID: https://orcid.org/0000-0001-7880-8577)
- James McMahon (ORCID: https://orcid.org/0000-0003-1460-5572)
- Jori Symons (ORCID: https://orcid.org/0000-0001-6560-1577)
- Rory A. Shepherd (ORCID: https://orcid.org/0009-0001-2215-2510)
Institutions
- The Royal Melbourne Hospital (AU)
- The University of Melbourne (AU)
- University of California, San Francisco (US)
- Peter MacCallum Cancer Centre (AU)
- University Medical Center Utrecht (NL)
- Peter Doherty Institute (AU)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1038/s41467-025-60001-2
- Citations
- 20
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 20.73
Funders
- amfAR, The Foundation for AIDS Research
- Delaney AIDS Research Enterprise
- Australian Centre for HIV and Hepatitis Virology Research
- Medical Research Council
- National Health and Medical Research Council
- National Institute of Allergy and Infectious Diseases
- Institute of Infection and Immunity