CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells.
METHODS
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.
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Alicia
A
Algeciras-Schimnich
Stacey R
SR
Vlahakis
Angelina
A
Villasis-Keever
Timothy
T
Gomez
Carrie J
CJ
Heppelmann
German
G
Bou
Carlos V
CV
Paya
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D015658:HIV Infections / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases