IMAI Shosuke Kochi University, Dpt of Mol.Microbiol.Infect., Professor, 医学部, 教授 (60232592)
MAEDA Akihiko Kochi University, Dpt of Pediatrics, Instructor, 医学部, 助手 (50335931)
|Budget Amount *help
¥4,000,000 (Direct Cost : ¥4,000,000)
Fiscal Year 2003 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 2002 : ¥2,300,000 (Direct Cost : ¥2,300,000)
Chronic active Epstein-Barr virus(EBV) infection(CAEBV) is a lethal T-or NK-lymphoproliferative disease often occurring in children. This study aimed to clarify the unknown pathogenesis of CAEBV, from which the establishment of a novel remedial strategy against the disease will also benefit.
The approach undertaken in this study is to seek for a latent EBV gene(s) resposible for uncontrolled T-or NK-cell-proliferation, which can functionally replace the role of entire EBV genome in the virus-positive T-or NK-cell lines derived from patients with CAEBV. We prepared improved self-inactivating retroviral vectors(SIN-RVs) that can express individual EBV latent genes, e.g., EBNA1, LMP1, LMP2A, BARF0, A73, RPMS1 and EBERs. Also, we successfully constructed an EBNA1 mutant, and incorporated it into the fiber-replaced adenovirus type 5 vector(Adv5/35f-DNE1). Adv5/35f-DNE1 proved that the EBNA1 mutant efficiently eradicates EBV episomes from infected cells and concomitantly impedes the virus-dependent aggressive growth phenotypes of EBV-positive T-or NK-cell lines, thereby indicating that our EBNA1 mutant can act as a dominant-negative(dn) EBNA1.
Based on the above data, we have just entered the final aspect of experiments to identify the EBV latent gene(s) essential to T-or NK-cell-proliferation. In parallel, we are invetigating now into whether our dnEBNA1 will provide an additional therapeutic molecule specifically targeting EBV-associated malignancies, by some ways including animal experiments.