Friday, March 18, 2011

Inflammation and EBV infection may promote XMRV spread in humans

NF-B Activation Stimulates Transcription and Replication of Retrovirus XMRV in Human B-Lineage and Prostate Carcinoma Cells

Shuhei Sakakibara,1* Kaori Sakakibara,2 and Giovanna Tosato1, Journal of Virology, April 2011:

Laboratory of Cellular Oncology,1 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 8 November 2010/ Accepted 20 January 2011

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.

* Corresponding author. Mailing address: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4134, Bethesda, MD 20892-1907. Phone: (301) 594-9597. Fax: (301) 594-9585. E-mail:
Published ahead of print on 26 January 2011.

Journal of Virology, April 2011

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