2005 Fiscal Year Final Research Report Summary
Novel therapeutic strategy against chronic active Epstein-Barr virus (EBV) infection
| Project/Area Number |
16591036
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kochi University |
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Principal Investigator |
WAKIGUCHI Hiroshi Kochi University, Department of Pediatrics, Professor, 医学部, 教授 (10116519)
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| Co-Investigator(Kenkyū-buntansha) |
MAEDA Akihiko Kochi University, Department of Pediatrics, Instructor, 医学部, 助手 (50335931)
KURODA Masayuki Kochi University, Department of Microbiology and Infection, Instructor, 医学部, 助手 (00253005)
IMAI Shosuke Kochi University, Department of Microbiology and Infection, Professor, 医学部, 教授 (60232592)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Epstein-Barr virus (EBV) / chronic active EBV infection / dominant-negative EBNA1 / gene therapy |
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| Research Abstract |
Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is a life-threatening disease that occurs more often in children than in adults and that is associated with unlimited T- or NK-cell proliferation infected by EBV. CAEBV is usually refractory to the conventional cancer chemotherapy and currently available anti-herpesvirus drugs. This research aimed to exploit a novel treatment effective against uncontrollable EBV disorders including CAEBV. In this study, we targeted EBV nuclear antigen (EBNA) 1, a latent viral protein essential to maintain EBV episomes in infected proliferating cells, and constructed a mutant that potentially inhibits the EBNA 1 function. Using this mutant EBNAI1 we examined whether it eradicates EBV episomes from infected cells, particularly from T/NK cells derived from CAEBV, and suppresses aggressive cell growth in association with virus eradication. Results obtained are as follows.
1.Adenovirus vector-mediated transduction of the mutant gene rapidly and striki
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ngly reduced EBV genomic loads in various EBV-converted cell lines and naturally EBV-harboring Burkitt's lymphoma (BL) cells. In addition, BL cells that lost virus episomes by the mutant EBNA1 expression showed significantly impaired growth in vitro and in vivo. This outcome indicated that the EBNA1 mutant can function as dominant-negative EBNA1(DNE1).
2.The DNE1 transduction also successfully suppressed the malignant growth of EBV-carrying T/NK cells established from patients with CAEBV or nasal lymphoma in vitro, in association with the elimination of viral episomes.
3.DNE1 was further validated to exert the anti-EBV effects through three different mechanisms : (1)competitive inhibition of wtEBNA1 binding to oriP, (2)decrease of de novo wtEBNA1 synthesis due to suppression of Qp, and (3)depletion of intracellular wtEBNA1 molecules by heterodimer formation. These results strongly suggest that the mutant can efficiently impedes the EBV-dependent malignant phenotypes in cells. Therefore, DNE1 will afford an additional therapeutic strategy specifically targeting EBV-associated malignant diseases, including CAEB V. Less
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