The Journal of Experimental Medicine
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Published online 5 March 2001.
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© The Rockefeller University Press, 0022-1007/2001/3/651/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 5, March 5, 2001 651-660

Brief Definitive Report

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

Yoshiharu Miuraa,b, Naoko Misawaa, Naoyoshi Maedaa, Yoshio Inagakic, Yuetsu Tanakad, Mamoru Itoe, Nobuhiko Kayagakif, Naoki Yamamotoc, Hideo Yagitaf, Hidehiro Mizusawab, and Yoshio Koyanagia
a Department of Virology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
b Department of Neurology, Tokyo Medical and Dental University, Tokyo, Japan
c Department of Microbiology, Tokyo Medical and Dental University, Tokyo, Japan
d Department of Infectious Disease and Immunology, Okinawa-Asia Research Center of Medical Science, University of the Ryukyus, Okinawa, Japan
e Central Institute for Experimental Animals, Kawasaki, Japan
f Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Correspondence to: Yoshio Koyanagi, Department of Virology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Tel:81-22-717-8210 Fax:81-22-717-8212 E-mail:koyanagi{at}mail.cc.tohoku.ac.jp.

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.

Key Words: HIV-1, apoptosis, TRAIL, hu-PBL-NOD-SCID mouse, TUNEL


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