TNF-related apoptosis-inducing ligand (TRAIL) induces neuronal apoptosis in HIV-encephalopathy.
Neuronal loss is, frequently found in brains of patients with human immunodeficiency virus (HIV)-encephalopathy. Extensive apoptosis of neurons is probably involved in the development of HIV-encephalopathy. The present study was designed to investigate the mechanism of neuronal apoptosis. For this purpose, we examined autopsy brains of two patients with HIV-encephalopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and active forms of caspase-3- and -8-positive cells, including neurons, were found in the perivascular regions of the brains. In these regions, TNF-related apoptosis-inducing ligand (TRAIL)+ macrophages were also observed. We also examined brains of HIV-1-infected mouse model inoculated with human cells. In these brains, TUNEL+ neurons were also found in the perivascular region, the site where infiltrated HIV-1-infected and TRAIL-expressing macrophages were observed. Using an in vitro-culture system, we also demonstrated that the HIV-1-infected monocyte-derived macrophages preferentially expressed TRAIL and that the addition of HIV-1-infected macrophages or human TRAIL-overexpressing mouse cells to cultured mouse primary neurons/glia resulted in neuronal apoptosis. Our results suggest the involvement of TRAIL expressed on HIV-1-infected macrophages in the induction of neuronal apoptosis in infected brain.
Miura
Yoshiharu
Y
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Japan. ymiura@mail.cc.tohoku.ac.jp
Koyanagi
Yoshio
Y
Mizusawa
Hidehiro
H
D015526:AIDS Dementia Complex / Q000473:pathology*; D000328:Adult; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis; D002478:Cells, Cultured; D015497:HIV-1; D006801:Humans; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism / Q000637:transplantation / Q000821:virology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases