Transforming growth factor-beta-mediated regulation of BK virus gene expression

Abstract

The increasing prevalence of BK virus (BKV)-associated diseases in immunosuppressed patients has prompted an investigation of the immune response to BKV, especially the role of cytokines in regulating viral replication. We examined the effect of TGF-β, a cytokine that is stimulated by certain immunosuppressive therapies, on BKV gene expression during lytic infection of renal proximal tubule epithelial cells. Viral gene expression, and specifically the activity of the BKV early promoter, is regulated by TGF-β in a strain-dependent manner. Promoter activity is upregulated in the presence of TGF-β for the TU strain of BKV, and not for the Dik, Dunlop, or Proto-2 strains. Using site-directed mutagenesis, we have identified a small segment of the TU promoter that is required for stimulation in response to TGF-β. These results demonstrate that BKV strains can respond differently to cytokine treatment and suggest that TGF-β may play a role in the reactivation of BKV. © 2008 Elsevier Inc. All rights reserved.