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J Virol. 2011 Apr;85(7):3179-86. doi: 10.1128/JVI.02333-10. Epub 2011 Jan 26.

NF-kappaB activation stimulates transcription and replication of retrovirus XMRV in human B-lineage and prostate carcinoma cells.

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1
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4134, Bethesda, MD 20892-1907, USA. sakakibs@mail.nih.gov

Abstract

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.

PMID:
21270144
PMCID:
PMC3067858
DOI:
10.1128/JVI.02333-10
[Indexed for MEDLINE]
Free PMC Article
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