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

Autor: Pardons M; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium., Cole B; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium., Lambrechts L; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium.; BioBix, Department of Data Analysis and Mathematical Modelling, Faculty of Bioscience Engineering, Ghent University, 9000, Ghent, Belgium., van Snippenberg W; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium., Rutsaert S; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium., Noppe Y; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium., De Langhe N; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium., Dhondt A; Department of Nephrology, Ghent University Hospital, 9000, Ghent, Belgium., Vega J; Arcturus Therapeutics, 10628 Science Center Drive, Suite 250, San Diego, 92121, CA, USA., Eyassu F; Computational biology, Johnson and Johnson, 2340, Beerse, Belgium., Nijs E; Janssen infectious diseases and diagnostics, Johnson and Johnson, 2340, Beerse, Belgium., Van Gulck E; Janssen infectious diseases and diagnostics, Johnson and Johnson, 2340, Beerse, Belgium., Boden D; Janssen Biopharma, Johnson and Johnson, South San Francisco, 94080, CA, USA., Vandekerckhove L; HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000, Ghent, Belgium. linos.vandekerckhove@ugent.be.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 18; Vol. 14 (1), pp. 8397. Date of Electronic Publication: 2023 Dec 18.
DOI: 10.1038/s41467-023-44020-5
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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