CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells

Alicia Algeciras-Schimnich, Stacey Rizza, Angelina Villasis-Keever, Timothy Gomez, Carrie J. Heppelmann, German Bou, Carlos V. Paya

Research output: Contribution to journalArticle

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Abstract

Design: HIV Env interaction with the corresponding chemokine receptor dictates the molecular mechanism of death of both HIV-infected and uninfected primary CD4 T cells. CXCR4/T tropic HIV virus (X4) triggers CD4 T cell death through a caspase independent mechanism, whereas CCR5/M tropic HIV virus (R5) HIV triggers a caspase dependent death. In the present study, we have investigated the pathway whereby R5 Env-CR5 interactions lead to a caspase dependent cell death. Methods: CD4 T cells were infected with X4 or R5 HIV strains, or were mock infected. After infection, cells were treated with caspase inhibitors or decoys of death receptor signaling pathways and cell viability was analyzed. The role of R5 HIV Env in induction of cell death of uninfected T cells was analyzed by co-culturing uninfected CD4 T cells with R5 Env expressing cells in the absence or presence of various inhibitors of death receptor signaling. Results: Infection of CD4 T cells with R5, but not with X4 HIV strains results in the activation of caspase-8 and cell death that is reversed by a decoy of the Fas receptor. Isolated activation of CCR5 by membrane-bound, or soluble R5 Env causes a Fas- and caspase-8 dependent death also of uninfected CD4 T cells. Additional studies demonstrate that isolated CCR5 activation by R5 Env leads to both de novo expression of FasL and induction of susceptibility to Fas-mediated apoptosis in resting primary CD4 T cells. Conclusions: These results ascribe to CCR5 a novel role in activating the Fas pathway and caspase-8 as well as triggering FasL production when activated by R5 Env, ultimately causing CD4 T cell death.

Original languageEnglish (US)
Pages (from-to)1467-1478
Number of pages12
JournalAIDS
Volume16
Issue number11
DOIs
StatePublished - Jul 26 2002

Fingerprint

Caspase 8
HIV
Apoptosis
T-Lymphocytes
Cell Death
Caspases
Death Domain Receptors
Viruses
CD95 Antigens
Caspase Inhibitors
Chemokine Receptors
Infection
Cell Survival
Membranes

Keywords

  • AIDS
  • Apoptosis
  • Chemokines
  • Immunodeficiency diseases
  • T lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Algeciras-Schimnich, A., Rizza, S., Villasis-Keever, A., Gomez, T., Heppelmann, C. J., Bou, G., & Paya, C. V. (2002). CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells. AIDS, 16(11), 1467-1478. https://doi.org/10.1097/00002030-200207260-00003

CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells. / Algeciras-Schimnich, Alicia; Rizza, Stacey; Villasis-Keever, Angelina; Gomez, Timothy; Heppelmann, Carrie J.; Bou, German; Paya, Carlos V.

In: AIDS, Vol. 16, No. 11, 26.07.2002, p. 1467-1478.

Research output: Contribution to journalArticle

Algeciras-Schimnich, A, Rizza, S, Villasis-Keever, A, Gomez, T, Heppelmann, CJ, Bou, G & Paya, CV 2002, 'CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells', AIDS, vol. 16, no. 11, pp. 1467-1478. https://doi.org/10.1097/00002030-200207260-00003
Algeciras-Schimnich, Alicia ; Rizza, Stacey ; Villasis-Keever, Angelina ; Gomez, Timothy ; Heppelmann, Carrie J. ; Bou, German ; Paya, Carlos V. / CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells. In: AIDS. 2002 ; Vol. 16, No. 11. pp. 1467-1478.
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AU - Rizza, Stacey

AU - Villasis-Keever, Angelina

AU - Gomez, Timothy

AU - Heppelmann, Carrie J.

AU - Bou, German

AU - Paya, Carlos V.

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N2 - Design: HIV Env interaction with the corresponding chemokine receptor dictates the molecular mechanism of death of both HIV-infected and uninfected primary CD4 T cells. CXCR4/T tropic HIV virus (X4) triggers CD4 T cell death through a caspase independent mechanism, whereas CCR5/M tropic HIV virus (R5) HIV triggers a caspase dependent death. In the present study, we have investigated the pathway whereby R5 Env-CR5 interactions lead to a caspase dependent cell death. Methods: CD4 T cells were infected with X4 or R5 HIV strains, or were mock infected. After infection, cells were treated with caspase inhibitors or decoys of death receptor signaling pathways and cell viability was analyzed. The role of R5 HIV Env in induction of cell death of uninfected T cells was analyzed by co-culturing uninfected CD4 T cells with R5 Env expressing cells in the absence or presence of various inhibitors of death receptor signaling. Results: Infection of CD4 T cells with R5, but not with X4 HIV strains results in the activation of caspase-8 and cell death that is reversed by a decoy of the Fas receptor. Isolated activation of CCR5 by membrane-bound, or soluble R5 Env causes a Fas- and caspase-8 dependent death also of uninfected CD4 T cells. Additional studies demonstrate that isolated CCR5 activation by R5 Env leads to both de novo expression of FasL and induction of susceptibility to Fas-mediated apoptosis in resting primary CD4 T cells. Conclusions: These results ascribe to CCR5 a novel role in activating the Fas pathway and caspase-8 as well as triggering FasL production when activated by R5 Env, ultimately causing CD4 T cell death.

AB - Design: HIV Env interaction with the corresponding chemokine receptor dictates the molecular mechanism of death of both HIV-infected and uninfected primary CD4 T cells. CXCR4/T tropic HIV virus (X4) triggers CD4 T cell death through a caspase independent mechanism, whereas CCR5/M tropic HIV virus (R5) HIV triggers a caspase dependent death. In the present study, we have investigated the pathway whereby R5 Env-CR5 interactions lead to a caspase dependent cell death. Methods: CD4 T cells were infected with X4 or R5 HIV strains, or were mock infected. After infection, cells were treated with caspase inhibitors or decoys of death receptor signaling pathways and cell viability was analyzed. The role of R5 HIV Env in induction of cell death of uninfected T cells was analyzed by co-culturing uninfected CD4 T cells with R5 Env expressing cells in the absence or presence of various inhibitors of death receptor signaling. Results: Infection of CD4 T cells with R5, but not with X4 HIV strains results in the activation of caspase-8 and cell death that is reversed by a decoy of the Fas receptor. Isolated activation of CCR5 by membrane-bound, or soluble R5 Env causes a Fas- and caspase-8 dependent death also of uninfected CD4 T cells. Additional studies demonstrate that isolated CCR5 activation by R5 Env leads to both de novo expression of FasL and induction of susceptibility to Fas-mediated apoptosis in resting primary CD4 T cells. Conclusions: These results ascribe to CCR5 a novel role in activating the Fas pathway and caspase-8 as well as triggering FasL production when activated by R5 Env, ultimately causing CD4 T cell death.

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