| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Research Abstract |
We previously reported the establishment of novel mouse strains with defective T and B cells as well as innate immunological functions associated with NK, macrophage, and complement and showed that all mutant mouse strains efficiently received human PBL (peripheral blood leukocyte) engraftment (hu-PBL-scid-mouse) (J. Virol. 71 : 2417-2424, 1997). Of these chimeric mice, hu-PBL-NOD-scid mice, efficient HIV-1 infection was observed after intraperitoneal injection. High levels of viremia (more than 1〜100 ng/ml of gag p24) were obtained by infection with a macrophage-tropic HIV-1 strain, JR-FL. Peak levels of the viremia were observed at 2 weeks post infection and the antigenemia disappeared 4 weeks after infection. In these HIV-1 infected mice, human CD3+/CD4+ and CD3+/CD8+ T cells proliferated up to 2 weeks after infection. In mouse spleen especially, white pulps were reconstructed and HIV_<gag> p24+ cells accumulated in the region where apoptotic cells were also observed. In addition to human T cells, human CD68+ macrophages were also reconstituted in the mouse spleen. These results suggested that the hu-PBL-NOD-scid mouse would be useful to investigate HIV-1 pathogenesis in tissues where human T cells and macrophages coexist. Thus, we started to examine whether the specific signals through molecules such as FasL, TNF, or/and TRAIL are involved in the pathogenesis. Double staining with TUNEL and anti-FasL, anti-TNF, or anti-TRAIL, respectively, revealed that the apoptotic cells were frequently found in conjugation with TRAIL+ cells. On the other hand, FasL+ cells or TNF+ cells were not associated with the apoptotic cells. Further analysis confirmed that the apoptotic and the adjacent TRAIL+ cells were both CD4+ human cells. These results suggest that, in the absence of specific immunity, many of the HIV-1 uninfected CD4+ T cells undergo apoptosis through the TRAIL signal in HIV-1 infected lymphoid organ during primary viremia.
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