Nature Communications (Dec 2023)

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,
  • Linos Vandekerckhove

DOI
https://doi.org/10.1038/s41467-023-44020-5
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 18

Abstract

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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.