Selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

Shringar Rao, Cynthia Lungu, Raquel Crespo, Thijs H. Steijaert, Alicja Gorska, Robert-Jan Palstra, Henrieke A. B. Prins, Wilfred Ijcken, Yvonne M. Mueller, Jeroen J. A. Kampen, Annelies Verbon, Peter D. Katsikis, Charles A. B. Boucher, Casper Rokx, Rob A. Gruters and Tokameh Mahmoudi ()
Additional contact information
Shringar Rao: Erasmus University Medical Center
Cynthia Lungu: Erasmus University Medical Center
Raquel Crespo: Erasmus University Medical Center
Thijs H. Steijaert: Erasmus University Medical Center
Alicja Gorska: Erasmus University Medical Center
Robert-Jan Palstra: Erasmus University Medical Center
Henrieke A. B. Prins: Erasmus University Medical Center
Wilfred Ijcken: Erasmus University Medical Center
Yvonne M. Mueller: Erasmus University Medical Center
Jeroen J. A. Kampen: Erasmus University Medical Center
Annelies Verbon: Erasmus University Medical Center
Peter D. Katsikis: Erasmus University Medical Center
Charles A. B. Boucher: Erasmus University Medical Center
Casper Rokx: Erasmus University Medical Center
Rob A. Gruters: Erasmus University Medical Center
Tokameh Mahmoudi: Erasmus University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract An innovative approach to eliminate HIV-1-infected cells emerging out of latency, the major hurdle to HIV-1 cure, is to pharmacologically reactivate viral expression and concomitantly trigger intracellular pro-apoptotic pathways in order to selectively induce cell death (ICD) of infected cells, without reliance on the extracellular immune system. In this work, we demonstrate the effect of DDX3 inhibitors on selectively inducing cell death in latent HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1 (PLWHIV). We used single-cell FISH-Flow technology to characterise the contribution of viral RNA to inducing cell death. The pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3 and upregulation of IFNβ. DDX3 inhibition also resulted in the downregulation of BIRC5, critical to cell survival during HIV-1 infection, and selectively induced apoptosis in viral RNA-expressing CD4+ T cells but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir by quantitation of HIV-1 RNA, by FISH-Flow, RT-qPCR and TILDA. This study provides proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards the elimination of the inducible reservoir.

Date: 2021
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DOI: 10.1038/s41467-021-22608-z

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