Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4+ T cells in HIV-1-infected hu-PBL-NOD-SCID mice.
Apoptosis is a key for CD4+ T cell destruction in HIV-1-infected patients. In this study, human peripheral blood lymphocyte (PBL)-transplanted nonobese diabetic (NOD)-severe combined immunodeficient (SCID) (hu-PBL-NOD-SCID) mice were used to examine in vivo apoptosis after HIV-1 infection. As the hu-PBL-NOD-SCID mouse model allowed us to see extensive infection with HIV-1 and to analyze apoptosis in human cells in combination with immunohistological methods, we were able to quantify the number of apoptotic cells with HIV-1 infection. As demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), massive apoptosis was predominantly observed in virus-uninfected CD4+ T cells in the spleens of HIV-1-infected mice. A combination of TUNEL and immunostaining for death-inducing tumor necrosis factor (TNF) family molecules indicated that the apoptotic cells were frequently found in conjugation with TNF-related apoptosis-inducing ligand (TRAIL)-expressing CD3+CD4+ human T cells. Administration of a neutralizing anti-TRAIL mAb in HIV-1-infected mice markedly inhibited the development of CD4+ T cell apoptosis. These results suggest that a large number of HIV-1-uninfected CD4+ T cells undergo TRAIL-mediated apoptosis in HIV-infected lymphoid organs.
Department of Virology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Y
Y
Miura
N
N
Misawa
N
N
Maeda
Y
Y
Inagaki
Y
Y
Tanaka
M
M
Ito
N
N
Kayagaki
N
N
Yamamoto
H
H
Yagita
H
H
Mizusawa
Y
Y
Koyanagi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D006085:Graft Survival; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D020287:In Situ Nick-End Labeling; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000378:metabolism / Q000473:pathology / Q000821:virology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D017252:CD3 Complex; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha