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Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes
Stacey R. Vlahakis, … , Ronald G. Collman, Carlos V. Paya
Stacey R. Vlahakis, … , Ronald G. Collman, Carlos V. Paya
Published January 15, 2001
Citation Information: J Clin Invest. 2001;107(2):207-215. https://doi.org/10.1172/JCI11109.
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Article

Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes

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Abstract

There is considerable confusion concerning the mechanism of lymphocyte death during HIV infection. During the course of HIV infection, M-tropic viruses (R5) that use CCR5 chemokine coreceptors frequently evolve to T-tropic viruses (X4) that use CXCR4 receptors. In this study we show that activation of the CD4 or CCR5 receptor by R5 HIVenv causes a caspase 8–dependent death of both uninfected and infected CD4 T cells. In contrast, CXCR4 activation by X4 HIVenv induces a caspase-independent death of both uninfected CD4 and CD8 T cells and infected CD4 cells. These results suggest that activation of the chemokine receptor by HIVenv determines the mechanism of death for both infected and uninfected T lymphocytes.

Authors

Stacey R. Vlahakis, Alicia Algeciras-Schimnich, German Bou, Carrie J. Heppelmann, Angelina Villasis-Keever, Ronald G. Collman, Carlos V. Paya

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Figure 1

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CCR5 activation induces a caspase-dependent death of CD4 T cells. (a) CD...
CCR5 activation induces a caspase-dependent death of CD4 T cells. (a) CD4 T cells were incubated with 293T cells transfected with empty vector or 293T cells expressing the HIVJRFL-env (R5env), either untreated or treated with soluble CD4 at different concentrations (sCD4). 293T cells were lysed and blotted by duo, tropic anti-gp160 to verify envelope expression (left panel). CD4 T cells were left untreated, pretreated with Z-IETD (a caspase 8 inhibitor) or Z-LHED (a caspase 9 inhibitor) before incubation with 293T cells expressing empty vector or R5env (right panel). (b) CD4 T cells treated or not treated with Z-VAD, SDF1α, or MIP1β were incubated with 293T cells expressing R5env or empty vector pretreated or not pretreated with sCD4, respectively. (c) CD4 T cells were treated with IgG-matched isotype control, anti-CD4 Leu-3a (αCD4 Ab), or anti-CCR5 MAB183 (αCCR5 Ab), followed by their cross-linking with goat anti-mouse Ab’s. Each point was assessed for caspase-dependent death (Z-VAD) as well as for Fas susceptibility (αFas). (d) CD4 T cells from a healthy donor with the CCR5 Δ32 mutation or from a control donor lacking the Δ32 CCR5 deletion were pretreated or not pretreated with Z-VAD and coincubated with 293T cells expressing R5env or empty vector, pretreated or not pretreated with sCD4.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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