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.

Avian reovirus σA-modulated suppression of lactate dehydrogenase and upregulation of glutaminolysis and the mTOC1/eIF4E/HIF-1α pathway to enhance glycolysis and the TCA cycle for virus replication

“…HIF-1 activation is a general phenomenon in human infectious diseases caused by hypoxia-dependent mechanisms (Werth et al, 2010). However, an earlier study suggested that HIF-1α binds to the BK polyomavirus promoter and increases the amount of BK polyomavirus DNA (Signorini et al, 2016), which indicates that virus-mediated triggering of HIF-1α might be a general phenomenon. This is the first report to indicate that ARV σA upregulates HIF-1α through activation of two distinct pathways.…”

Hypoxic microenvironment shapes HIV-1 replication and latency

“…While most in vitro studies on viral replication utilize cells cultured at atmospheric oxygen levels (~20% O 2 ), the vast majority of human tissues have oxygen levels much lower than this (referred to as hypoxia). Hypoxia can have opposing effects on viral proliferation, inducing the replication of Epstein–Barr virus 3 – 5 , Kaposi sarcoma-associated herpesvirus 4 , 6 , human T-cell leukemia virus 7 , and human polyomavirus BK 8 , while suppressing the infectivity of adenovirus 9 and Moloney murine leukemia virus 10 . These contrasting effects are likely to reflect the variable oxygen tension at the sites of virus replication and the complex interplay between viruses and their hosts 11 .…”

Human polyomaviruses genomes in clinical specimens of colon cancer patients

“…The program of TaqMan Real Time PCR assay provides four steps: 2 min at 50°C, 15 min at 95°C followed by 40 cycles of 15 s at 95°C and 1 min at 60°C. The composition of the reaction mix, the thermal profile, the primers and the probe sequences were previously published 21–24 . The primers and probes sequences were also reported in the Table 2.…”

“…The composition of the reaction mix, the thermal profile, the primers and the probe sequences were previously published. [21][22][23][24] The primers and probes sequences were also reported in the Table 2. A quantitative Real-Time PCR targeting the β-globin gene was conducted to calculate the percentage of the infected cells, as previously described.…”