Efficient mRNA delivery to resting T cells to reverse HIV latency
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
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.


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