Efficient mRNA delivery to resting T cells to reverse HIV latency

作者：Paula M. Cevaal, Stanislav Kan, Bridget M. Fisher, Michael A. Moso, Abigail Er Qi Tan, Haiyin Liu, Abdalla Ali, Kiho Tanaka, Rory A. Shepherd, Youry Kim, Jesslyn Ong, Denzil Furtado, Marvin Holz, Damian F. J. Purcell, Joshua Casan, Thomas J. Payne, Wei Zhao, Mohamed Fareh, James McMahon, Steven G. Deeks, Rebecca Hoh, Sushama Telwatte, Colin W. Pouton, Angus P. R. Johnston, Frank Caruso, Jori Symons, Sharon R. Lewin, Michael J. Roche · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60001-2 · 被引用次数：32 · 研究领域：HIV Research and Treatment、RNA Interference and Gene Delivery、Immune Cell Function and Interaction

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.