Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells

Sharma, Biswa Nath; Li, Ruomei; Bernhoff, Eva; Gutteberg, Tore Jarl; Rinaldo, Christine Hanssen

doi:10.1016/j.antiviral.2011.07.012

Cited by 80 publications

(65 citation statements)

References 34 publications

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“…However, the treatment of cells with LVFX did not change cell attachment, the growth and viability of the cells, or LDH concentrations in the supernatants. These findings were consistent with previous reports that ofloxacin, a fluoroquinolone, does not affect the number of cultured primary human renal proximal tubular epithelial cells (31). Shimoda and Kato demonstrated previously that LVFX does not exacerbate retinal degeneration induced by phototoxicity in mouse eyes (32).…”

Section: Discussionsupporting

confidence: 82%

“…These findings suggest the possibility that LVFX may also inhibit infection by other viruses such as RSV and influenza virus. Recent reports have demonstrated that the fluoroquinolones LVFX and ofloxacin inhibit human polyomavirus BK (BKV) replication in primary human kidney cells (31). Further experiments are needed to study this possibility.…”

Section: Discussionmentioning

confidence: 99%

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Levofloxacin Inhibits Rhinovirus Infection in Primary Cultures of Human Tracheal Epithelial Cells

Yamaya

Nishimura²,

Hatachi

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTRespiratory virus infections, including infections with rhinoviruses (RVs), are related to exacerbations of chronic obstructive pulmonary disease (COPD). A new quinolone antibiotic, levofloxacin (LVFX), has been used to treat bacterial infections that cause COPD exacerbations as well as bacterial infections that are secondary to viral infection in COPD patients. However, the inhibitory effects of LVFX on RV infection and RV infection-induced airway inflammation have not been studied. We examined the effects of LVFX on type 14 rhinovirus (RV14) (a major human RV) infection of human tracheal epithelial cells pretreated with LVFX. LVFX pretreatment reduced the RV14 titer, the level of cytokines in the supernatant, the amount of RV14 RNA in the cells after RV14 infection, and the cells' susceptibility to RV14 infection. LVFX pretreatment decreased the mRNA level of intercellular adhesion molecule 1 (ICAM-1), a receptor for RV14, in the cells and the concentration of the soluble form of ICAM-1 in the supernatant before RV14 infection. LVFX pretreatment also decreased the number and the fluorescence intensity of the acidic endosomes from which RV14 RNA enters the cytoplasm. LVFX pretreatment inhibited the activation of nuclear factor κB proteins, including p50 and p65, in nuclear extracts. LVFX pretreatment did not reduce the titers of RV2 (a minor human RV) but reduced the titers of RV15 (a major human RV). These results suggest that LVFX inhibits major-group rhinovirus infections in part by reducing ICAM-1 expression levels and the number of acidic endosomes. LVFX may also modulate airway inflammation in rhinoviral infections.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Levofloxacin Inhibits Rhinovirus Infection in Primary Cultures of Human Tracheal Epithelial Cells

Yamaya

Nishimura²,

Hatachi

et al. 2012

Antimicrob Agents Chemother

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“…There are no drugs that can reduce polyomavirus replication efficiently in vivo (42)(43)(44). Since the inhibition of TAg function results in impairing virus replication (45)(46)(47), the single amino acid V392 might be a target for the inhibition of JCV replication.…”

Section: Discussionmentioning

confidence: 99%

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Takahashi

Sekizuka

Fukumoto

et al. 2017

J Virol

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JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominantnegative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited.IMPORTANCE DNA viruses generally have lower mutation frequency than RNA viruses, and the detection of quasispecies in JCV has rarely been reported. In the present study, a next-generation sequencer identified a JCV quasispecies with an amino acid substitution in the T antigen in patients with PML. In vitro studies showed that the mutation strongly repressed the expression of JC viral proteins and reduced the viral replication. However, because the frequency of the mutation was low in each case, the total expression of virus proteins was sustained in vivo. Thus, JC virus replicates in PML lesions in the presence of a mutant virus which is able to repress virus replication.

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“…PyVAN and PyVHC have a significant impact on morbidity and graft and patient survival 11, 12, 13, 14, 15, 16, 17, 18. Despite considerable virologic research 19, 20, 21, 22, 23, randomized clinical studies either are lacking or failed to demonstrate effective antiviral therapies 24. In kidney transplantation (KT), high‐level BKPyV viruria and viremia have been identified as markers of progression to PyVAN 25, thus current management strategies recommend screening KTRs for viremia followed by reducing immunosuppression 26, 27, 28.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

Cioni

Leboeuf

Comoli

et al. 2016

American Journal of Transplantation

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Uncontrolled BK polyomavirus (BKPyV) replication in kidney transplant recipients (KTRs) causes polyomavirus‐associated nephropathy and allograft loss. Reducing immunosuppression is associated with clearing viremia and nephropathy and increasing BKPyV‐specific T cell responses in most patients; however, current immunoassays have limited sensitivity, target mostly CD4+ T cells, and largely fail to predict onset and clearance of BKPyV replication. To characterize BKPyV‐specific CD8+ T cells, bioinformatics were used to predict 9mer epitopes in the early viral gene region (EVGR) presented by 14 common HLAs in Europe and North America. Thirty‐nine EVGR epitopes were experimentally confirmed by interferon‐γ enzyme‐linked immunospot assays in at least 30% of BKPyV IgG–seropositive healthy participants. Most 9mers clustered in domains, and some were presented by more than one HLA class I, as typically seen for immunodominant epitopes. Specific T cell binding using MHC class I streptamers was demonstrated for 21 of 39 (54%) epitopes. In a prospective cohort of 118 pediatric KTRs, 19 patients protected or recovering from BKPyV viremia were experimentally tested, and 13 epitopes were validated. Single HLA mismatches were not associated with viremia, suggesting that failing immune control likely involves multiple factors including maintenance immunosuppression. Combining BKPyV load and T cell assays using immunodominant epitopes may help in evaluating risk and reducing immunosuppression and may lead to safe adoptive T cell transfer.

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Fluoroquinolones inhibit human polyomavirus BK (BKV) replication in primary human kidney cells

Cited by 80 publications

References 34 publications

Levofloxacin Inhibits Rhinovirus Infection in Primary Cultures of Human Tracheal Epithelial Cells

Levofloxacin Inhibits Rhinovirus Infection in Primary Cultures of Human Tracheal Epithelial Cells

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

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