Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4134, Bethesda, MD 20892-1907, USA.
J Virol. 2011 Apr;85(7):3179-86. doi: 10.1128/JVI.02333-10. Epub 2011 Jan 26.
Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-κB activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-α), which activates NF-κB, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-α and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-κB activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-κB binding sites (designated κB-1 and κB-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-κB component p65/RelA. Mutation of the κB-1 site, but not the κB-2 site, impaired responsiveness to TNF-α and LMP1 in reporter assays. A mutant XMRV with a mutation at the κB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-α and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the κB-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-κB activation may promote XMRV spread in humans.
嗜性鼠白血病病毒相关病毒 (XMRV) 是一种与前列腺癌和慢性疲劳综合征相关的γ逆转录病毒。在这里，我们报告 NF-κB 的激活可以显著增加 XMRV 的产生。炎症细胞因子肿瘤坏死因子-α（TNF-α）激活 NF-κB，显著增加 XMRV 感染细胞中的病毒 Gag 蛋白产生。报告基因检测显示，TNF-α和 Epstein-Barr 病毒（EBV）潜伏膜蛋白 1（LMP1），一种内在的 NF-κB 激活剂，增加了长末端重复（LTR）依赖的 XMRV 转录。我们在 XMRV 的 LTR U3 区域鉴定了两个 NF-κB 结合位点（分别命名为 κB-1 和 κB-2），并证明这两个位点都与 NF-κB 成分 p65/RelA 结合。κB-1 位点的突变，但不是 κB-2 位点的突变，削弱了报告基因检测中对 TNF-α和 LMP1 的反应性。在 LTR 上具有 κB-1 位点突变的突变型 XMRV 在前列腺癌细胞系 LNCaP、DU145 和 PC-3、HEK293 细胞、EBV 永生化细胞系 IB4 和 Burkitt 淋巴瘤细胞系 BJAB 中的复制效率明显低于野生型 XMRV。这些结果表明，TNF-α 和 EBV LMP1 通过 XMRV LTR 中的 κB-1 位点增强前列腺癌和 B 细胞系中的 XMRV 复制，提示炎症、EBV 感染和其他导致 NF-κB 激活的情况可能促进 XMRV 在人类中的传播。
