Interaction between the Hypoxia Inducible Factor 1 alpha and the human polyomavirus BK:a risk factor for the development of polyomavirus associated nephropathy

INTRODUCTION: BK polyomavirus (BKV) has a worldwide seroprevalence of about 90%. After the primary infection, it establishes a life-long latency within the urogenital tract. The severe immunological impairment occurring in transplant kidney recipients leads to BKV reactivation that may result in the polyomavirus associated nephropathy (PVAN). During transplantation, the kidneys are subjected to hypoxic conditions, driven by the action of Hypoxia Inducible Factor (HIF). It has been proved that HIF isoform 1-α (HIF-1α) may interact with several viruses, but till now the scientific literature does not present any information regarding the interaction between BKV and HIF-1α. The aim of the study is to investigate the possible interaction between HIF-1α and BKV, and its potential effect on the pathogenesis of PVAN. MATHERIALS AND METHODS: The expression of HIF- 1α was evaluated at the mRNA level in 17 kidney paraffin-embedded tissue samples, from BKV+ PVAN, BKV+ NOT PVAN, and BKV- patients, by means of RNA retrotranscription and subsequent specific real time PCR. Luciferase and Cromathin Immunoprecipitation (ChIP) assays were performed on BKV transfected VERO cells, to verify the interaction between the viral promoter and HIF-1α. The effect of hypoxia on BKV replication was assessed by evaluating BKV load in BKV infected VERO cells, treated and not treated with Cobalt Chloride (CoCl2). RESULTS: HIF-1α expression was 13.6 folds higher in BKV+ PVAN tissues and 0.7 folds higher in BKV+ NOT PVAN tissues compared to BKV- tissues. Luciferase activity was higher ranging from 2 to 6 fold (p<0.05) when VERO cells were transfected with both BKV and HIF-1α, compared to those transfected only with BKV; ChIP analysis showed the structural binding between the viral promoter and HIF-1α. BKV load was 5 fold increased in infected cells treated with CoCl2 treatment compared to infected cells without CoCl2 treatment. DISCUSSION AND CONCLUSION: the interaction between BKV and HIF-1α was observed both in vitro and ex vivo. HIF-1α, that is stabilized by the hypoxia conditions, occurring during the transplantation, is able to bind the BKV promoter and to enhance BKV replication. Consequently, the hypoxia represents a risk factor for the PVAN developing in kidney transplant recipients.