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Systems analysis by mass cytometry identifies susceptibility of latent HIV-infected T cells to targeting of p38 and mTOR pathways

Linda E. Fong, Victor L. Bass, Serena Spudich, Kathryn Miller-Jensen
doi: https://doi.org/10.1101/371922
Linda E. Fong
1Department of Biomedical Engineering, Yale University, New Haven, CT, USA
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Victor L. Bass
2Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
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Serena Spudich
3Department of Neurology, Yale University, New Haven, CT, USA
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Kathryn Miller-Jensen
1Department of Biomedical Engineering, Yale University, New Haven, CT, USA
2Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
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  • For correspondence: kathryn.miller-jensen@yale.edu
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Abstract

Efforts to cure HIV are hindered by viral persistence in latently infected memory CD4+ T cells. Targeting T cell death pathways dysregulated by HIV infection offers a novel approach for eradication of the latent reservoir. To identify potential therapeutic targets, we compared signaling and apoptosis in uninfected and latently infected primary cultured CD4+ central memory T cells by mass cytometry following T cell receptor stimulation. We found that HIV-infected cells were sensitized to activation of pro-apoptotic p38 kinase signaling via p53, and to inhibition of anti-apoptotic mTOR kinase signaling, even without HIV protein expression. Simultaneous targeting of p38 and mTOR kinases in resting CD4+ T cells from virally-suppressed HIV+ patients ex vivo reduced cell-associated HIV RNA and DNA. Our results demonstrate how systems biology approaches are useful for identifying novel therapeutic approaches to treat HIV latency, and further suggest that it may be possible to deplete latent HIV-infected T cells without viral reactivation.

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Posted July 19, 2018.
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Systems analysis by mass cytometry identifies susceptibility of latent HIV-infected T cells to targeting of p38 and mTOR pathways
Linda E. Fong, Victor L. Bass, Serena Spudich, Kathryn Miller-Jensen
bioRxiv 371922; doi: https://doi.org/10.1101/371922
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Systems analysis by mass cytometry identifies susceptibility of latent HIV-infected T cells to targeting of p38 and mTOR pathways
Linda E. Fong, Victor L. Bass, Serena Spudich, Kathryn Miller-Jensen
bioRxiv 371922; doi: https://doi.org/10.1101/371922

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