Eradication of epstein-barr virus episome and associated inhibition of infected tumor cell growth by adenovirus vector-mediated transduction of dominant-negative EBNA1

Md Nasimuzzaman, Masayuki Kuroda, Sumitaka Dohno, Takenobu Yamamoto, Keiji Iwatsuki, Shigenobu Matsuzaki, Rashel Mohammad, Wakako Kumita, Hiroyuki Mizuguchi, Takao Hayakawa, Hiroyuki Nakamura, Takahiro Taguchi, Hiroshi Wakiguchi, Shosuke Imai

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1), a latent viral protein consistently expressed in infected proliferating cells, is essentially required in trans to maintain EBV episomes in cells. We constructed a mutant (mt) EBNA1 and examined whether it exerted dominant-negative effects on maintenance of the viral episome thereby leading to abrogation of EBV-infected tumor cell growth. Using lymphocyte and epithelial cell lines converted with neomycin-resistant recombinant EBV (rEBV) as models, adenovirus vector-mediated transduction of mtEBNA1, but not LacZ, brought about rapid and striking reductions in rEBV-derived wild-type EBNA1 levels and viral genomic loads in converted lines of three major viral latencies. This outcome was further validated at the single-cell level by cellular loss of G418 resistance and viral signals in situ. The mtEBNA1 transduction significantly impaired growth of naturally EBV-harboring Burkitt lymphoma cells in vitro and in vivo, largely in association with the eradication of viral episomes. Expression of mtEBNA1 per se caused no detectable cytotoxicity in EBV-uninfected cells. These results indicate that mtEBNA1 can act as a dominant-negative effector that efficiently impedes the EBV-dependent malignant phenotypes in cells regardless of viral latency or tissue origin. The mutant will afford an additional therapeutic strategy specifically targeting EBV-associated malignancies.

Original languageEnglish
Pages (from-to)578-590
Number of pages13
JournalMolecular Therapy
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 2005

Keywords

  • Adenovirus vector
  • EBNA1 mutant
  • EBV episome eradication
  • Epstein-Barr virus
  • Gene therapy
  • Tumor growth inhibition

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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