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 nonob ese 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 immunohistolo gical methods, we were able to quantify the number of apoptotic cells with HIV-1 infection. As demonstrated by terminal deoxynucleotidyl transferase-m ediated dUTP nick-end labeling (TUNEL), massive apoptosis was predominantly observed in virus-uninfected CD4(+) T cells in the spleens of HIV-1-infect ed 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 li gand (TRAIL)-expressing CD3(+)CD4(+) human T cells. Administration of a neu tralizing anti-TRAIL mAb in HIV-1-infected mice markedly inhibited the deve lopment of CD4(+) T cell apoptosis. These results suggest that a large numb er of HIV-1-uninfected CD4(+) T cells undergo TRAIL-mediated apoptosis in H IV-infected lymphoid organs.