Efficient mRNA delivery to resting T cells to reverse HIV latency

Cevaal, PM; Kan, S; Fisher, BM; Moso, MA; Tan, A; Liu, H; Ali, A; Tanaka, K; Shepherd, RA; Kim, Y; Ong, J; Furtado, DL; Holz, M; Purcell, DFJ; Casan, JML; Payne, T; Zhao, W; Fareh, M; McMahon, JH; Deeks, SG; Hoh, R; Telwatte, S; Pouton, CW; Johnston, APR; Caruso, F; Symons, J; Lewin, SR; Roche, M

Author(s): Cevaal, PM; Kan, S; Fisher, BM; Moso, MA; Tan, A; Liu, H; Ali, A; Tanaka, K; Shepherd, RA; Kim, Y; Ong, J; Furtado, DL; Holz, M; Purcell, DFJ; Casan, JML; Payne, T; Zhao, W; Fareh, M; McMahon, JH; Deeks, SG; Hoh, R; Telwatte, S; Pouton, CW; Johnston, APR; Caruso, F; Symons, J; Lewin, SR; Roche, M;
Details: Publication Year 2025-05-29,Volume 16,Issue #1,Page 4979
Journal Title: Nature Communications
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: Humans; *Virus Latency/genetics; *CD4-Positive T-Lymphocytes/virology/metabolism; *HIV-1/genetics/physiology; *HIV Infections/virology/therapy/immunology; Nanoparticles/chemistry; *RNA, Messenger/genetics/administration & dosage/metabolism; tat Gene Products, Human Immunodeficiency Virus/genetics/metabolism; Lipids/chemistry; Transcription, Genetic; Liposomes
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41467-025-60001-2
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-60001-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-06-03 07:20:21

Last Modified: 2025-06-03 07:20:41