Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression

Cell Death Differ. 2003 Nov;10(11):1240-52. doi: 10.1038/sj.cdd.4401289.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / enzymology
  • Acquired Immunodeficiency Syndrome / immunology
  • Acquired Immunodeficiency Syndrome / virology
  • Animals
  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD4-Positive T-Lymphocytes / virology
  • Carrier Proteins / metabolism
  • Caspases / immunology*
  • Cell Death / drug effects
  • Cell Death / immunology
  • Disease Models, Animal
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Fas Ligand Protein
  • Humans
  • Interleukins / pharmacology
  • Macaca mulatta
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Mitochondria / virology
  • Pan troglodytes
  • Proto-Oncogene Proteins*
  • Signal Transduction / physiology*
  • Simian Acquired Immunodeficiency Syndrome / enzymology*
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / immunology*
  • Simian Immunodeficiency Virus / pathogenicity
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • T-Lymphocytes / virology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology
  • Viral Load
  • bcl-2 Homologous Antagonist-Killer Protein
  • fas Receptor / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BAK1 protein, human
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Carrier Proteins
  • Enzyme Inhibitors
  • FASLG protein, human
  • Fas Ligand Protein
  • Interleukins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • fas Receptor
  • Caspases