Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a murine model of HIV central nervous system infection.
HIV-1 infection in the brain induces neuronal apoptosis leading to HIV-associated dementia. To explore the underlying mechanism, we developed a murine model by using human peripheral blood mononuclear cell (PBMC)-transplanted nonobese diabetic (NOD)-severe combined immunodeficiency (SCID) (hu-PBMC-NOD-SCID) mice. Administration of lipopolysaccharide (LPS) to HIV-1-infected hu-PBMC-NOD-SCID mice induced infiltration of HIV-1-infected human cells into the perivascular region of the brain and neuronal apoptosis was found in macrophage (M)-tropic but not T cell (T)-tropic HIV-1-infected brains. The apoptotic neurons were frequently colocalized with the HIV-1-infected macrophages that expressed tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Administration of a neutralizing antibody against human TRAIL but not human TNF-alpha or Fas ligand (FasL) blocked the neuronal apoptosis in the HIV-1-infected brain. These results strongly suggest a critical contribution of TRAIL expressed on HIV-1-infected macrophages to neuronal apoptosis.
Miura
Yoshiharu
Y
Department of Virology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Misawa
Naoko
N
Kawano
Yuji
Y
Okada
Hiroshi
H
Inagaki
Yoshio
Y
Yamamoto
Naoki
N
Ito
Mamoru
M
Yagita
Hideo
H
Okumura
Ko
K
Mizusawa
Hidehiro
H
Koyanagi
Yoshio
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002490:Central Nervous System / Q000821:virology*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009474:Neurons / Q000166:cytology* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha