Nature communications · 2025
Efficient mRNA delivery to resting T cells to reverse HIV latency.
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Cevaal Paula M, Kan Stanislav, Fisher Bridget M, Moso Michael A, Tan Abigail, Liu Haiyin, Ali Abdalla, Tanaka Kiho, Shepherd Rory A, Kim Youry, Ong Jesslyn, Furtado Denzil L, Holz Marvin, Purcell Damian F J, Casan Joshua M L, Payne Thomas, Zhao Wei, Fareh Mohamed, McMahon James H, Deeks Steven G, Hoh Rebecca, Telwatte Sushama, Pouton Colin W, Johnston Angus P R, Caruso Frank, Symons Jori, Lewin Sharon R, Roche Michael
Аннотация
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.