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BK Polyomavirus MicroRNA Levels in Exosomes Are Modulated by Non-Coding Control Region Activity and Down-Regulate Viral Replication When Delivered to Non-Infected Cells Prior to Infection.

  • Martelli F Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy. martelli.francesco85@gmail.com.
  • Wu Z Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, CH-4003 Basel, Switzerland. zongsong.wu@unibas.ch.
  • Delbue S Department of Biomedical, Surgical and Dental Sciences, University of Milan, I-20100 Milano, Italy. serena.delbue@unimi.it.
  • Weissbach FH Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, CH-4003 Basel, Switzerland. fabian.weissbach@unibas.ch.
  • Giulioli MC Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy. maria.chiara2591@gmail.com.
  • Ferrante P Department of Biomedical, Surgical and Dental Sciences, University of Milan, I-20100 Milano, Italy. pasquale.ferrante@unimi.it.
  • Hirsch HH Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, CH-4003 Basel, Switzerland. hans.hirsch@unibas.ch.
  • Giannecchini S Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy. simone.giannecchini@unifi.it.
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  • 2018-09-12
Published in:
  • Viruses. - 2018
BK virus
exosomes
immunosuppression
microRNA
non-coding control region
persistence
polyomavirus
Animals
Antiviral Agents
BK Virus
COS Cells
Chlorocebus aethiops
Exosomes
Humans
Immunocompromised Host
MicroRNAs
RNA, Viral
Urine
Viral Load
Virus Replication
English In immunosuppressed patients, BKPyV-variants emerge carrying rearranged non-coding control-regions (rr-NCCRs) that increase early viral gene region (EVGR) expression and replication capacity. BKPyV also encodes microRNAs, which have been reported to downregulate EVGR-encoded large T-antigen transcripts, to decrease viral replication in infected cells and to be secreted in exosomes. To investigate the interplay of NCCR and microRNAs, we compared archetype- and rr-NCCR-BKPyV infection in cell culture. We found that laboratory and clinical rr-NCCR-BKPyV-strains show higher replication rates but significantly lower microRNA levels than archetype virus intracellularly and in exosomes. To investigate whether rr-NCCR or increased EVGR activity modulated microRNA levels, we examined the (sp1-4)NCCR-BKPyV, which has an archetype NCCR-architecture but shows increased EVGR expression due to point mutations inactivating one Sp1 binding site. We found that microRNA levels following (sp1-4)NCCR-BKPyV infection were as low as in rr-NCCR-variants. Thus, NCCR rearrangements are not required for lower miRNA levels. Accordingly, Sp1 siRNA knock-down decreased microRNA levels in archetype BKPyV infection but had no effect on (sp1-4)- or rr-NCCR-BKPyV. However, rr-NCCR-BKPyV replication was downregulated by exosome preparations carrying BKPyV-microRNA prior to infection. To explore the potential relevance in humans, urine samples from 12 natalizumab-treated multiple sclerosis patients were analysed. In 7 patients, rr-NCCR-BKPyV were detected showing high urine BKPyV loads but low microRNAs levels, whereas the opposite was seen in 5 patients with archetype BKPyV. We discuss the results in a dynamic model of BKPyV replication according to NCCR activity and exosome regulation, which integrates immune selection pressure, spread to new host cells and rr-NCCR emergence.
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  • English
Open access status
gold
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Persistent URL
https://folia.unifr.ch/global/documents/53976
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