| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
LP-BM5 murine leukemia virus (MuLV) infection causes severe immunodeficiency termed murine AIDS (MAIDS). The acyclic nucleoside phosphonates, (R)-9-(2-p hosphonylmethoxypropyl) adenine (PMPA) and 9-(2-phosphonylmethoxyethyl) adenine (PMEA) were examined, in comparison with zidovudine (AZT), for their inhibitory effect on the development of MAIDS.Although no significant difference in inhibition of LP-BM5 MuLV replication was identified between PMPA and PMEA in cell cultures, PMPA was obviously less cytotoxic to the host lymphocytes. None of the mice treated in vivo with 5 or 25 mg/kg of PMPA or 25 mg/kg of PMEA developed MAIDS at 5 weeks after viral infection. However, at 9 weeks, none of the 25 mg/kg PMPA-treated mice progressed to MAIDS, except for one that developed mild MAIDS, whereas PMEA, even at 100 mg/kg, could not prevent disease progression. MAIDS-associated activation of lymphocytes and viral replication were drastically inhibited by PMPA treatment. Furthermore, the structure of follicular dendritic cells (FDC) and germinal center was normally conserved. These results indicate that PMPA is a highly effective antiretroviral agent in vivo. However, the 25 mg/kg of PMPA treatment starting from 24 hr after viral infection could not inhibit the viral replication and development of MAIDS.Furthermore, in vivo treatment by viral Ag-pulsed dendritic cells (DCs) showed no remarkable therapeutic effect against MAIDS.However, CD8+ killer cells activated by the Ag-pulsed DCs in vitro exhibited temporal anti-MAIDS effect only when they were inoculated directly into lymph node. These results suggest that useful mediators that can selectively activate CD8+ T cells for a long time are absolutely required to treat LP-BM5 MuLV-infected mice.
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