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

In immunosuppressed patients, -variants emerge carrying rearranged non-coding control-regions ( ) that increase early viral gene region (EVGR) expression and replication capacity. also encodes microRNAs, which have been reported to downregulate EVGR-encoded large T-antigen transcripts, to decrease v...

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Bibliographic Details
Published in:	Viruses Vol. 10; no. 9; p. 466
Main Authors:	Martelli, Francesco, Wu, Zongsong, Delbue, Serena, Weissbach, Fabian H, Giulioli, Maria Chiara, Ferrante, Pasquale, Hirsch, Hans H, Giannecchini, Simone
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 30-08-2018 MDPI
Subjects:	Acquired immune deficiency syndrome AIDS Animals Antigen T (large) Antigens Antiviral Agents - analysis Antiviral Agents - metabolism BK virus BK Virus - growth & development BK Virus - isolation & purification Blood & organ donations Cell culture Cercopithecus aethiops COS Cells Deoxyribonucleic acid Disease DNA Exosomes Exosomes - chemistry Gene expression Genomes HIV Human immunodeficiency virus Humans Immunocompromised Host immunosuppression Infections Laboratories microRNA MicroRNAs MicroRNAs - analysis MicroRNAs - metabolism miRNA Monoclonal antibodies Multiple sclerosis Mutation non-coding control region persistence polyomavirus Replication RNA, Viral - analysis RNA, Viral - metabolism siRNA Sp1 protein Transcription factors Transplants & implants Urine Urine - virology Viral Load Virology Virus Replication Italy Switzerland polyomavirus exosomes non-coding control region immunosuppression microRNA persistence BK virus
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Summary:	In immunosuppressed patients, -variants emerge carrying rearranged non-coding control-regions ( ) that increase early viral gene region (EVGR) expression and replication capacity. 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 and microRNAs, we compared archetype- and infection in cell culture. We found that laboratory and clinical -strains show higher replication rates but significantly lower microRNA levels than archetype virus intracellularly and in exosomes. To investigate whether or increased EVGR activity modulated microRNA levels, we examined the ( ) , which has an archetype -architecture but shows increased EVGR expression due to point mutations inactivating one Sp1 binding site. We found that microRNA levels following ( ) infection were as low as in -variants. Thus, rearrangements are not required for lower miRNA levels. Accordingly, Sp1 siRNA knock-down decreased microRNA levels in archetype infection but had no effect on ( )- or . However, replication was downregulated by exosome preparations carrying -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, were detected showing high urine loads but low microRNAs levels, whereas the opposite was seen in 5 patients with archetype . We discuss the results in a dynamic model of replication according to activity and exosome regulation, which integrates immune selection pressure, spread to new host cells and emergence.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Both authors contributed equally to this study.
ISSN:	1999-4915 1999-4915
DOI:	10.3390/v10090466