title: Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells.
abstract: Reactivation of human polyomavirus BK (BKV) may cause polyomavirus-associated nephropathy or polyomavirus-associated hemorrhagic cystitis in renal- or bone marrow-transplant patients, respectively. Lack of treatment options has led to exploration of fluoroquinolones that inhibit topoisomerase II and IV in prokaryotes and possibly large T-antigen (LT-ag) helicase activity in polyomavirus. We characterized the effects of ofloxacin and levofloxacin on BKV replication in the natural host cells - primary human renal proximal tubular epithelial cells (RPTECs). Ofloxacin and levofloxacin inhibited BKV load in a dose-dependent manner yielding a ∼90% inhibition at 150 μg/ml. Ofloxacin at 150 μg/ml inhibited LT-ag mRNA and protein expression from 24h post infection (hpi). BKV genome replication was 77% reduced at 48 hpi and a similar reduction was found in VP1 and agnoprotein expression. At 72 hpi, the reduction in genome replication and protein expression was less pronounced. A dose-dependent cytostatic effect was noted. In infected cells, 150 μg/ml ofloxacin led to a 26% and 6% inhibition of cellular DNA replication and total metabolic activity, respectively while 150 μg/ml levofloxacin affected this slightly more, particularly in uninfected cells. Cell counting and xCELLigence results revealed that cell numbers were not reduced. In conclusion, ofloxacin and levofloxacin inhibit but do not eradicate BKV replication in RPTECs. At a concentration of ofloxacin giving ∼90% inhibition in BKV load, no significant cytotoxicity was observed. This concentration can be achieved in urine and possibly in the kidneys. Our results support a mechanism involving inhibition of LT-ag expression or functions but also suggest inhibition of cellular enzymes.
authors.affiliation: Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Biswa Nath
authors.initials: BN
authors.lastname: Sharma
authors.forename: Ruomei
authors.initials: R
authors.lastname: Li
authors.forename: Eva
authors.initials: E
authors.lastname: Bernhoff
authors.forename: Tore Jarl
authors.initials: TJ
authors.lastname: Gutteberg
authors.forename: Christine Hanssen
authors.initials: CH
authors.lastname: Rinaldo
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001739:BK Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D004847:Epithelial Cells / Q000821:virology; D024841:Fluoroquinolones / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000821:virology; D027601:Polyomavirus Infections / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D024841:Fluoroquinolones