Efficient mRNA delivery to resting T cells to reverse HIV latency

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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.

Introduction

Recent advances in mRNA and lipid nanoparticle (LNP) technology have allowed for the development of new vaccines and therapeutics, holding great promise for gene therapy. In 2018, patisiran (Onpattro) was approved as the first LNP-based therapeutic for the delivery of silencing (si)RNA for transthyretin-mediated amyloidosis¹. The same platform has since been used to deliver mRNA to generate two of the most effective vaccines against COVID-19 (Comirnaty (Pfizer/BioNTech) and Spikevax (Moderna)). More recently, LNPs have been used to deliver mRNA for CRISPR-Cas9 gene editing in vivo, which was found to be safe in human clinical trials². These advances have triggered enormous interest in the use of mRNA-LNPs as versatile therapeutics, including for infectious diseases such as HIV.

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