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Induction of 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 van Ijcken, Yvonne M. Mueller, Jeroen J. A. van Kampen, Annelies Verbon, Peter D. Katsikis, Charles A. B. Boucher, Casper Rokx, Rob A. Gruters, Tokameh Mahmoudi
doi: https://doi.org/10.1101/2020.08.26.266726
Shringar Rao
1Department of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Cynthia Lungu
2Department of Viroscience, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Raquel Crespo
1Department of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Thijs H. Steijaert
1Department of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Alicja Gorska
1Department of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Robert-Jan Palstra
1Department of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Henrieke A. B. Prins
3Department of Internal Medicine, section of Infectious Diseases, Erasmus University Medical Center, Rg-530, PO Box 2040 3000CA Rotterdam, The Netherlands
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Wilfred van Ijcken
4Erasmus Center for Biomics, Erasmus University Medical Center, Ee-671, PO Box 2040, 3000CA Rotterdam, Netherlands
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Yvonne M. Mueller
5Department of Immunology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Jeroen J. A. van Kampen
2Department of Viroscience, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Annelies Verbon
3Department of Internal Medicine, section of Infectious Diseases, Erasmus University Medical Center, Rg-530, PO Box 2040 3000CA Rotterdam, The Netherlands
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Peter D. Katsikis
5Department of Immunology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Charles A. B. Boucher
2Department of Viroscience, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Casper Rokx
3Department of Internal Medicine, section of Infectious Diseases, Erasmus University Medical Center, Rg-530, PO Box 2040 3000CA Rotterdam, The Netherlands
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Rob A. Gruters
2Department of Viroscience, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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Tokameh Mahmoudi
1Department of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
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  • For correspondence: t.mahmoudi@erasmusmc.nl
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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 DEAD-box polypeptide 3, X-Linked (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). RNA sequencing analysis revealed that while overall gene expression was minimally dysregulated, DDX3 inhibition in independent donor CD4+ T cells led to significant downregulation of BIRC5 and HSPB1A, genes critical to cell survival during HIV-1 infection. We used single-cell FISH-Flow technology to characterise latency reversal and the contribution of viral RNA to inducing cell death; pharmacological targeting of DDX3 induced HIV-1 RNA expression, resulting in phosphorylation of IRF3, upregulation of IFNβ and selective induction of apoptosis in viral RNA-expressing CD4+ T cells from PLWHIV but not bystander cells. DDX3 inhibitor treatment of CD4+ T cells from PLWHIV in an in vitro culture model over five days resulted in an approximately 50% reduction of the inducible latent HIV-1 reservoir as determined by quantitation of CA HIV-1 RNA, by TILDA, as well as by FISH-Flow technology. Our data support the translation of DDX3 inhibitor class compounds into HIV-1 curative strategies and provide proof of concept for pharmacological reversal of latency coupled to induction of apoptosis towards elimination of the inducible reservoir.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 01, 2021.
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Induction of 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 van Ijcken, Yvonne M. Mueller, Jeroen J. A. van Kampen, Annelies Verbon, Peter D. Katsikis, Charles A. B. Boucher, Casper Rokx, Rob A. Gruters, Tokameh Mahmoudi
bioRxiv 2020.08.26.266726; doi: https://doi.org/10.1101/2020.08.26.266726
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Induction of 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 van Ijcken, Yvonne M. Mueller, Jeroen J. A. van Kampen, Annelies Verbon, Peter D. Katsikis, Charles A. B. Boucher, Casper Rokx, Rob A. Gruters, Tokameh Mahmoudi
bioRxiv 2020.08.26.266726; doi: https://doi.org/10.1101/2020.08.26.266726

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