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

doi:10.1084/jem.193.5.651

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 Miura^a^,b, Naoko Misawa^a, Naoyoshi Maeda^a, Yoshio Inagaki^c, Yuetsu Tanaka^d, Mamoru Ito^e, Nobuhiko Kayagaki^f, Naoki Yamamoto^c, Hideo Yagita^f, Hidehiro Mizusawa^b, and Yoshio Koyanagi^a

^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
Department of Virology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.81-22-717-821281-22-717-8210

koyanagi{at}mail.cc.tohoku.ac.jp

Apoptosis is a key for CD4⁺ T cell destruction in HIV-1–infectedpatients. In this study, human peripheral blood lymphocyte (PBL)-transplantednonobese diabetic (NOD)-severe combined immunodeficient (SCID)(hu-PBL-NOD-SCID) mice were used to examine in vivo apoptosisafter HIV-1 infection. As the hu-PBL-NOD-SCID mouse model allowedus to see extensive infection with HIV-1 and to analyze apoptosisin human cells in combination with immunohistological methods,we were able to quantify the number of apoptotic cells withHIV-1 infection. As demonstrated by terminal deoxynucleotidyltransferase–mediated dUTP nick-end labeling (TUNEL), massiveapoptosis was predominantly observed in virus-uninfected CD4⁺T cells in the spleens of HIV-1–infected mice. A combinationof TUNEL and immunostaining for death-inducing tumor necrosisfactor (TNF) family molecules indicated that the apoptotic cellswere frequently found in conjugation with TNF-related apoptosis-inducingligand (TRAIL)-expressing CD3⁺CD4⁺ human T cells. Administrationof a neutralizing anti-TRAIL mAb in HIV-1–infected micemarkedly inhibited the development of CD4⁺ T cell apoptosis.These results suggest that a large number of HIV-1–uninfectedCD4⁺ T cells undergo TRAIL-mediated apoptosis in HIV-infectedlymphoid organs.

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

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