Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression.
Studies of human immunodeficiency virus (HIV) and nonhuman primate models of pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections have suggested that enhanced ex vivo CD4 T-cell death is a feature of pathogenic infection in vivo. However, the relative contributions of the extrinsic and intrinsic pathways to programmed T-cell death in SIV infection have not been studied. We report here that the spontaneous death rate of CD4+ T cells from pathogenic SIVmac251-infected rhesus macaques ex vivo is correlated with CD4 T-cell depletion and plasma viral load in vivo. CD4+ T cells from SIVmac251-infected macaques showed upregulation of the death ligand (CD95L) and of the proapoptotic proteins Bim and Bak, but not of Bax. Both CD4+ and CD8+ T cells from SIVmac251-infected macaques underwent caspase-dependent death following CD95 ligation. The spontaneous death of CD4+ and CD8+ T cells was not prevented by a decoy CD95 receptor or by a broad-spectrum caspase inhibitor (zVAD-fmk), suggesting that this form of cell death is independent of CD95/CD95L interaction and caspase activation. IL-2 and IL-15 prevented the spontaneous death of CD4+ and CD8+ T cells, whereas IL-10 prevented only CD8 T-cell death and IL-7 had no effect on T-cell death. Our results indicate that caspase-dependent and caspase-independent pathways are involved in the death of T cells in pathogenic SIVmac251-infected primates.
INSERM EMI-U 9922, Faculté Bichat-Claude Bernard, Paris, France.
D
D
Arnoult
F
F
Petit
J D
JD
Lelièvre
J D
JD
Lelièvie
D
D
Lecossier
A
A
Hance
V
V
Monceaux
B
B
Hurtrel
B
B
Huntrel
R
R
Ho Tsong Fang
J C
JC
Ameisen
J
J
Estaquier
D000163:Acquired Immunodeficiency Syndrome / Q000201:enzymology / Q000276:immunology / Q000821:virology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D007378:Interleukins / Q000494:pharmacology; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002679:Pan troglodytes; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000502:physiology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000472:pathogenicity; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D019562:Viral Load; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007378:Interleukins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor; D020169:Caspases