Stimulation of BK Virus DNA Replication by NFI Family Transcription Factors

Abstract

b BK polyomavirus (BKV) establishes persistent, low-level, and asymptomatic infections in most humans and causes polyomavirus-associated nephropathy (PVAN) and other pathologies in some individuals. The activation of BKV replication following kidney transplantation, leading to viruria, viremia, and, ultimately, PVAN, is associated with immune suppression as well as inflammation and stress from ischemia-reperfusion injury of the allograft, but the stimuli and molecular mechanisms leading to these pathologies are not well defined. The replication of BKV DNA in cell cultures is regulated by the viral noncoding control region (NCCR) comprising the core origin and flanking sequences, to which BKV T antigen (Tag), cellular proteins, and small regulatory RNAs bind. Six nuclear factor I (NFI) binding sites occur in sequences flanking the late side of the core origin (the enhancer) of the archetype virus, and their mutation, either individually or in toto, reduces BKV DNA replication when placed in competition with templates containing intact BKV NCCRs. NFI family members interacted with the helicase domain of BKV Tag in pulldown assays, suggesting that NFI helps recruit Tag to the viral core origin and may modulate its function. However, Tag may not be the sole target of the replication-modulatory activities of NFI: the NFIC/CTF1 isotype stimulates BKV template replication in vitro at low concentrations of DNA polymerase-␣ primase (Pol-primase), and the p58 subunit of Polprimase associates with NFIC/CTF1, suggesting that NFI also recruits Pol-primase to the NCCR. These results suggest that NFI proteins (and the signaling pathways that target them) activate BKV replication and contribute to the consequent pathologies caused by acute infection.

Outcomes of renal transplant recipients with BK virus infection and BK virus surveillance in the Auckland region from 2006 to 2012

“…A long CIT was identified as a potential risk factor for BKVN in our study, and is known to cause severe ischaemia-reperfusion injury resulting in intragraft inflammation, which in turn is found to stimulate BK polyomavirus DNA replication[34,35]. Acute rejection results in tubulointerstitial inflammation and typically leads to also an increased burden of immunosuppression.…”

Identification of MW Polyomavirus, a Novel Polyomavirus in Human Stool

“…Palindrome patterns were identified in MWPyV, but no additional LTAg binding sites were detected in this area. The regulatory region contained several predicted transcription factor binding sites, including multiple binding sites for four factors known to play a role in BKPyV viral transcription and regulation: Sp1, nuclear factor I (NFI), AP1, and C/EBP (29). Multiple binding sites were also identified for HNF-3, USF-2, and Oct-1.…”

Early and late promoters of BK polyomavirus, Merkel cell polyomavirus, Trichodysplasia spinulosa-associated polyomavirus and human polyomavirus 12 are among the strongest of all known human polyomaviruses in 10 different cell lines

“…While the presence of these receptors is essential for infection, cellular factors that bind the HPyV promoter or HPyV regulatory proteins will affect viral transcription and replication and effect viral production (e.g. Gorrill & Khalili, 2005;Feng et al, 2011;Ferenczy et al, 2013;Jordan et al, 2010;Liang et al, 2012;Marshall et al, 2012;Ravichandran & Major, 2006;Romagnoli et al, 2009;Safak & Khalili, 2001;Wang et al, 2012;White et al, 2014;Wollebo et al, 2012). Hence, these interactions will determine the cell tropism of the HPyV.…”