Efficient mRNA delivery to resting T cells to reverse HIV latency
Abstract
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.
Article Details
Authors (28)
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
Department of Medicine, University of California
Rebecca Hoh
Department of Medicine, University of California
Sushama Telwatte
Colin W. Pouton
Angus P. R. Johnston
Frank Caruso
Department of Chemical Engineering
Jori Symons
Sharon R. Lewin
Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Michael Roche