Both HIV-Infected and uninfected cells express TRAILshort, which confers TRAIL resistance upon bystander cells within the microenvironment

Zilin Nie, Fatma Aboulnasr, Sekar Natesampillai, Stephen P. Burke, Ashton Krogman, Gary D. Bren, Thomas D.Y. Chung, Jeff R. Anderson, Michele K. Smart, David J Katzmann, Govindarajan Rajagopalan, Nathan W Cummins, Andrew David Badley

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Abstract

TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.

Original languageEnglish (US)
Pages (from-to)1110-1123
Number of pages14
JournalJournal of Immunology
Volume200
Issue number3
DOIs
StatePublished - Feb 1 2018

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TNF-Related Apoptosis-Inducing Ligand
Cellular Microenvironment
HIV
TNF-Related Apoptosis-Inducing Ligand Receptors
Proteasome Endopeptidase Complex
Ubiquitin
Genomics

ASJC Scopus subject areas

  • Immunology

Cite this

Both HIV-Infected and uninfected cells express TRAILshort, which confers TRAIL resistance upon bystander cells within the microenvironment. / Nie, Zilin; Aboulnasr, Fatma; Natesampillai, Sekar; Burke, Stephen P.; Krogman, Ashton; Bren, Gary D.; Chung, Thomas D.Y.; Anderson, Jeff R.; Smart, Michele K.; Katzmann, David J; Rajagopalan, Govindarajan; Cummins, Nathan W; Badley, Andrew David.

In: Journal of Immunology, Vol. 200, No. 3, 01.02.2018, p. 1110-1123.

Research output: Contribution to journalArticle

Nie, Z, Aboulnasr, F, Natesampillai, S, Burke, SP, Krogman, A, Bren, GD, Chung, TDY, Anderson, JR, Smart, MK, Katzmann, DJ, Rajagopalan, G, Cummins, NW & Badley, AD 2018, 'Both HIV-Infected and uninfected cells express TRAILshort, which confers TRAIL resistance upon bystander cells within the microenvironment', Journal of Immunology, vol. 200, no. 3, pp. 1110-1123. https://doi.org/10.4049/jimmunol.1701113
Nie, Zilin ; Aboulnasr, Fatma ; Natesampillai, Sekar ; Burke, Stephen P. ; Krogman, Ashton ; Bren, Gary D. ; Chung, Thomas D.Y. ; Anderson, Jeff R. ; Smart, Michele K. ; Katzmann, David J ; Rajagopalan, Govindarajan ; Cummins, Nathan W ; Badley, Andrew David. / Both HIV-Infected and uninfected cells express TRAILshort, which confers TRAIL resistance upon bystander cells within the microenvironment. In: Journal of Immunology. 2018 ; Vol. 200, No. 3. pp. 1110-1123.
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AU - Natesampillai, Sekar

AU - Burke, Stephen P.

AU - Krogman, Ashton

AU - Bren, Gary D.

AU - Chung, Thomas D.Y.

AU - Anderson, Jeff R.

AU - Smart, Michele K.

AU - Katzmann, David J

AU - Rajagopalan, Govindarajan

AU - Cummins, Nathan W

AU - Badley, Andrew David

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