title: Interaction Between Human Polyomavirus BK and Hypoxia Inducible Factor-1 alpha.
abstract: BK polyomavirus (BKV) has a worldwide seroprevalence of approximately 90%. After primary infection, BKV establishes a life-long latency within the urogenital tract. The severe immunological impairment occurring in renal transplant recipients leads to BKV reactivation, which may result in polyomavirus associated nephropathy (PVAN). While the transplanted kidney is transiently unperfused, Hypoxia Inducible Factors (HIFs) mediate the cellular response to hypoxia. The α-subunit of HIF isoform 1 (HIF-1α) may interact with several viruses, but until now, there has been no information regarding the interaction between BKV and HIF-1α. The aim of this study is to investigate the possible interaction between HIF-1α and BKV and its potential effect on the pathogenesis of PVAN. Screening of 17 kidney tissue samples revealed that HIF-1α expression was 13.6-fold higher in PVAN tissues compared to control tissues. A luminometric assay in co-transfected African green monkey kidney cells (VERO) demonstrated BKV promoter activation ranging from two to sixfold (P < 0.05) when HIF-1α was over-expressed. A Chromatin ImmunoPrecipitation (ChIP) assay showed structural binding between the BKV promoter and HIF-1α. The amount of BKV DNA increased by threefold in VERO infected cells that were exposed to simulated hypoxia, compared to the cells not subjected to hypoxia. Both ex vivo and in vitro interactions between HIF-1α and BKV were observed, suggesting that HIF-1α, stabilized during transplantation, may be able to bind the BKV promoter and enhance BKV replication. Thus, hypoxia should be considered a risk factor for the development of PVAN in kidney transplant recipients.
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Signorini
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Croci
authors.affiliation: Department of Health Sciences, Unit of Pathology, University of Eastern Piedmont Novara, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Boldorini
authors.affiliation: Department of Microbiology and Parasitology, Biomedical Institute, Universidade Federal Fluminense, Brazil.
authors.forename: Rafael Brandao
authors.initials: RB
authors.lastname: Varella
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Elia
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carluccio
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Villani
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Bella
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ferrante
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milano, Milano, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Delbue
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001739:BK Virus / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism*; D001665:Binding Sites; D015687:Cell Hypoxia; D002522:Chlorocebus aethiops; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D005260:Female; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000821:virology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012307:Risk Factors; D014162:Transfection; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D015854:Up-Regulation; D014709:Vero Cells; D019562:Viral Load
chemical_list: D004279:DNA, Viral; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit