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<p>A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4<sup>+</sup> 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<sup>+</sup> T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4<sup>+</sup> 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<sup>+</sup> 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.</p>

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Efficient mRNA delivery to resting T cells to reverse HIV latency

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月29日

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

摘要

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.