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

ABSTRACT: Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-?B activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-?), which activates NF-?B, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-? and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-?B activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-?B binding sites (designated ?B-1 and ?B-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-?B component p65/RelA. Mutation of the ?B-1 site, but not the ?B-2 site, impaired responsiveness to TNF-? and LMP1 in reporter assays. A mutant XMRV with a mutation at the ?B-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-? and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the ?B-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-?B activation may promote XMRV spread in humans.

SUBMITTER: Sakakibara S 

PROVIDER: S-EPMC3067858 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature