Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3146-51. doi: 10.1073/pnas.0910717107. Epub 2010 Jan 26.
EBV causes infectious mononucleosis and is associated with certain malignancies. EBV nuclear antigen 1 (EBNA1) mediates EBV genome replication, partition, and transcription, and is essential for persistence of the viral genome in host cells. Here we demonstrate that Hsp90 inhibitors decrease EBNA1 expression and translation, and that this effect requires the Gly-Ala repeat domain of EBNA1. Hsp90 inhibitors induce the death of established, EBV-transformed lymphoblastoid cell lines at doses nontoxic to normal cells, and this effect is substantially reversed when lymphoblastoid cell lines are stably infected with a retrovirus expressing a functional EBNA1 mutant lacking the Gly-Ala repeats. Hsp90 inhibitors prevent EBV transformation of primary B cells, and strongly inhibit the growth of EBV-induced lymphoproliferative disease in SCID mice. These results suggest that Hsp90 inhibitors may be particularly effective for treating EBV-induced diseases requiring the continued presence of the viral genome.
EBV 引起传染性单核细胞增多症，并与某些恶性肿瘤有关。EBV 核抗原 1（EBNA1）介导 EBV 基因组复制、分配和转录，是病毒基因组在宿主细胞中持续存在所必需的。在这里，我们证明 HSP90 抑制剂降低 EBNA1 的表达和翻译，而这种效应需要 EBNA1 的甘-丙氨酸重复结构域。HSP90 抑制剂以不损伤正常细胞的剂量诱导已建立的 EBV 转化的淋巴母细胞系死亡，而当淋巴母细胞系稳定感染表达缺乏甘-丙氨酸重复的功能性 EBNA1 突变体的逆转录病毒时，这种效应会显著逆转。HSP90 抑制剂可防止 EBV 转化原代 B 细胞，并强烈抑制 SCID 小鼠中 EBV 诱导的淋巴组织增生性疾病的生长。这些结果表明，HSP90 抑制剂可能特别有效地治疗需要病毒基因组持续存在的 EBV 诱导疾病。
