J Virol. 2011 Jan 26. [Epub ahead of print]
Sakakibara S, Sakakibara K, Tosato G.:
Laboratory of Cellular Oncology, and Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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 TNFα, which activates NF-κB, significantly augmented viral Gag protein production in XMRV-infected cells.
Reporter assays showed that TNFα and Epstein-Barr virus LMP1 (latent membrane protein 1), an intrinsic NF-κB activator, increased LTR-dependent XMRV transcription. We identify two NF-κB binding sites (designated κB-1 and κB-2) in the long terminal repeat (LTR) U3 region of XMRV, and demonstrate 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 TNFα and LMP1 in reporter assays. A mutant XMRV at the κB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145 and PC3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4 and the Burkitt's lymphoma cell line BJAB.
These results demonstrate that TNFα 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 man.