Efficient mRNA delivery to resting T cells to reverse HIV latency
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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60001-2 |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |