Abstract
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.
Highlights
BK polyomavirus (BKPyV) is one of more than 10 human polyomaviruses (HPyV) and it infects>90% of the general human population without ill effects [1,2,3]
We examined the miRNA levels seen with theNCCR-BKPyV andNCCR-BKPyV, which, as outlined above, have an archetype architecture but show increased and decreased early viral gene region (EVGR) expression and viral replication, respectively
To investigate whether non-coding control region (NCCR) rearrangements or increased EVGR activity played a role in modulating the miRNA levels, we examined theNCCR-BKPyV, which has an archetype architecture but shows increased EVGR expression and viral replication due to point mutations inactivating the SP1-4 binding site upstream of the late viral gene region (LVGR) transcription start site [29,30] (Figure 1)
Summary
BK polyomavirus (BKPyV) is one of more than 10 human polyomaviruses (HPyV) and it infects>90% of the general human population without ill effects [1,2,3]. BK polyomavirus (BKPyV) is one of more than 10 human polyomaviruses (HPyV) and it infects. BKPyV causes nephropathy or haemorrhagic cystitis in immunocompromised patients, after kidney or allogeneic hematopoietic cell transplantation [4,5]. Antibody levels decline during adult life [9,10] unless significant re-exposure occurs which includes immunocompromised patients [11,12,13,14]. In kidney transplant or allogeneic hematopoietic cell transplant patients, high-level BKPyV replication precedes nephropathy or haemorrhagic cystitis, respectively [4,5]. Increased BKPyV reactivation rates have been observed in other solid organ transplant recipients and in HIV/AIDS patients [19,20,21].
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