Cytokine-mediated Regulation of BK Virus Replication.

Abstract

BK virus (BKV) is a member of the polyomavirus family that infects nearly the entire human population at an early age. Following a subclinical primary infection, BKV is able to establish a persistent infection in the kidney and urinary tract. Reactivation of BKV occurs in immunocompromised individuals and can lead to severe disease. BKV-associated diseases include polyomavirus nephropathy (PVN), a form of acute interstitial nephritis, and hemorrhagic cystitis (HC), an infection of the bladder characterized by inflammation and hematuria. PVN and HC are increasing in prevalence, likely due to the development of more potent immunosuppressive therapies. To better understand which components of the immune system are important for regulating BKV infection, we began to examine the effect of cytokines on virus replication. IFN-gamma has a strong inhibitory effect on BKV transcription, gene expression, and replication, but does not affect the kinetics of the viral life cycle or trafficking of the virus to the nucleus. IFN-gamma treatment inhibited gene expression of three different BKV strains similarly, suggesting that regulation by this cytokine is relevant for all viral strains. We have begun to further examine regulation of viral transcription by IFN-gamma to identify the specific factors involved and investigate changes in viral chromatin structure. In contrast to IFN-gamma, TGF-beta has an upregulatory effect on BKV strain TU early promoter activity. Three other strains examined were either unaffected or downregulated by TGF-beta treatment in a cell type-dependent manner. The TGF-beta response elements were mapped within the promoter of BKV TU. The viral strain- and cell type-dependent effects of TGF-beta demonstrate the complex nature in which BKV is regulated by cytokine signaling. Finally, we have begun to investigate the inability of archetype strains of BKV to replicate in tissue culture. Overall, our findings will help us to better understand BKV persistence in healthy individuals and reactivation in immunocompromised patients.