Potent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir

Marion Pardons, Basiel Cole, Laurens Lambrechts, Willem van Snippenberg, Sofie Rutsaert, Ytse Noppe, Nele De Langhe, Annemieke Dhondt, Jerel Vega, Filmon Eyassu, Erik Nijs, Ellen Van Gulck, Daniel Boden and Linos Vandekerckhove ()
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Marion Pardons: Ghent University Hospital, Ghent University
Basiel Cole: Ghent University Hospital, Ghent University
Laurens Lambrechts: Ghent University Hospital, Ghent University
Willem van Snippenberg: Ghent University Hospital, Ghent University
Sofie Rutsaert: Ghent University Hospital, Ghent University
Ytse Noppe: Ghent University Hospital, Ghent University
Nele De Langhe: Ghent University Hospital, Ghent University
Annemieke Dhondt: Ghent University Hospital
Jerel Vega: Arcturus Therapeutics
Filmon Eyassu: Computational biology, Johnson and Johnson
Erik Nijs: Janssen infectious diseases and diagnostics, Johnson and Johnson
Ellen Van Gulck: Janssen infectious diseases and diagnostics, Johnson and Johnson
Daniel Boden: Janssen Biopharma, Johnson and Johnson
Linos Vandekerckhove: Ghent University Hospital, Ghent University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The development of latency reversing agents that potently reactivate HIV without inducing global T cell activation would benefit the field of HIV reservoir research and could pave the way to a functional cure. Here, we explore the reactivation capacity of a lipid nanoparticle containing Tat mRNA (Tat-LNP) in CD4 T cells from people living with HIV undergoing antiretroviral therapy (ART). When combined with panobinostat, Tat-LNP induces latency reversal in a significantly higher proportion of latently infected cells compared to PMA/ionomycin (≈ 4-fold higher). We demonstrate that Tat-LNP does not alter the transcriptome of CD4 T cells, enabling the characterization of latently infected cells in their near-native state. Upon latency reversal, we identify transcriptomic differences between infected cells carrying an inducible provirus and non-infected cells (e.g. LINC02964, GZMA, CCL5). We confirm the transcriptomic differences at the protein level and provide evidence that the long non-coding RNA LINC02964 plays a role in active HIV infection. Furthermore, p24+ cells exhibit heightened PI3K/Akt signaling, along with downregulation of protein translation, suggesting that HIV-infected cells display distinct signatures facilitating their long-term persistence. Tat-LNP represents a valuable research tool for in vitro reservoir studies as it greatly facilitates the in-depth characterization of HIV reservoir cells’ transcriptome and proteome profiles.

Date: 2023
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DOI: 10.1038/s41467-023-44020-5

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