Trailshort protects against CD4 T cell death during acute HIV infection

Sekar Natesampillai; Ana C. Paim; Nathan W. Cummins; Aswath P. Chandrasekar; Gary D. Bren; Sharon R. Lewin; Hans Peter Kiem; Andrew D. Badley

doi:10.4049/jimmunol.1900271

Trailshort protects against CD4 T cell death during acute HIV infection

Sekar Natesampillai, Ana C. Paim, Nathan W. Cummins, Aswath P. Chandrasekar, Gary D. Bren, Sharon R. Lewin, Hans Peter Kiem, Andrew D. Badley

Medicine - Infectious Disease and International Medicine

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Abstract

CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

Original language	English (US)
Pages (from-to)	718-724
Number of pages	7
Journal	Journal of Immunology
Volume	203
Issue number	3
DOIs	https://doi.org/10.4049/jimmunol.1900271
State	Published - Aug 1 2019

Bibliographical note

Funding Information:
This work was supported by the Mayo Clinic Foundation (to A.C.P. and N.W.C.). S.R.L. was supported by the National Institutes of Health (NIH) Delaney AIDS Research Enterprise (Grants U19 AI096109 and UM1 AI126611-01) and the National Health and Medical Research Council (NHMRC) of Australia (NHMRC program grant and practitioner fellowship). A.D.B. was supported by the National Institute of Allergy and Infectious Diseases of the NIH (Grants AI110173 and AI120698). H.-P.K. is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright Ó 2019 by The American Association of Immunologists, Inc.

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title = "Trailshort protects against CD4 T cell death during acute HIV infection",

abstract = "CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.",

author = "Sekar Natesampillai and Paim, {Ana C.} and Cummins, {Nathan W.} and Chandrasekar, {Aswath P.} and Bren, {Gary D.} and Lewin, {Sharon R.} and Kiem, {Hans Peter} and Badley, {Andrew D.}",

note = "Funding Information: This work was supported by the Mayo Clinic Foundation (to A.C.P. and N.W.C.). S.R.L. was supported by the National Institutes of Health (NIH) Delaney AIDS Research Enterprise (Grants U19 AI096109 and UM1 AI126611-01) and the National Health and Medical Research Council (NHMRC) of Australia (NHMRC program grant and practitioner fellowship). A.D.B. was supported by the National Institute of Allergy and Infectious Diseases of the NIH (Grants AI110173 and AI120698). H.-P.K. is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the Jos{\'e} Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright {\'O} 2019 by The American Association of Immunologists, Inc.",

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doi = "10.4049/jimmunol.1900271",

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AU - Paim, Ana C.

AU - Cummins, Nathan W.

AU - Chandrasekar, Aswath P.

AU - Bren, Gary D.

AU - Lewin, Sharon R.

AU - Kiem, Hans Peter

AU - Badley, Andrew D.

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N2 - CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

AB - CD4 T cells from HIV-1 infected patients die at excessive rates compared to those from uninfected patients, causing immunodeficiency. We previously identified a dominant negative ligand that antagonizes the TRAIL-dependent pathway of cell death, which we called TRAILshort. Because the TRAIL pathway has been implicated in CD4 T cell death occurring during HIV-1 infection, we used short hairpin RNA knockdown, CRISPR deletion, or Abs specific for TRAILshort to determine the effect of inhibiting TRAILshort on the outcome of experimental acute HIV infection in vitro. Strikingly, all three approaches to TRAILshort deletion/inhibition enhanced HIV-induced death of both infected and uninfected human CD4 T cells. Thus, TRAILshort impacts T cell dynamics during HIV infection, and inhibiting TRAILshort causes more HIV-infected and uninfected bystander cells to die. TRAILshort is, therefore, a host-derived, host-adaptive mechanism to limit the effects of TRAIL-induced cell death. Further studies on the effects of TRAILshort in other disease states are warranted.

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ER -

Trailshort protects against CD4 T cell death during acute HIV infection

Abstract

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