BKTyper: Free Online Tool for Polyoma BK Virus VP1 and NCCR Typing

Martí-Carreras, Joan; Mineeva-Sangwo, Olga; Topalis, Dimitrios; Snoeck, Robert; Andrei, Gracíela; Maes, Piet

doi:10.3390/v12080837

Cited by 10 publications

(11 citation statements)

References 35 publications

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“…We downloaded all 510 complete BKPyV genomes from NCBI GenBank (accessed 16 August 2020) and removed any duplicate genomes from these data set to obtain 402 unique BKPyV genomes. These 402 BKPyV genomes were then classified into the 11 VP1 sequence subtypes and subgroups with BKTyper 1.0 ( 49 ). We next randomly selected 10 genomes from each of these subtypes or subgroups for inclusion in our phylogenetic analysis.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Generation of BK and JC Polyomavirus Defective Viral Genomes in Human Urine Samples Associated with Higher Viral Loads

Addetia

Phung

Bradley

et al. 2021

J Virol

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Defective viral genomes (DVGs) are parasitic viral sequences containing point mutations, deletions, or duplications that might interfere with replication. DVGs are often associated with viral passage at high multiplicities of infection in culture systems but have been increasingly reported in clinical specimens. To date however, only RNA viruses have been shown to contain DVGs in clinical specimens. Here, using direct deep sequencing with multiple library preparation strategies and confirmatory ddPCR of urine samples taken from immunosuppressed individuals, we show clinical BKPyV and JCPyV strains contain widespread genomic rearrangements across multiple loci that likely interfere with viral replication. BKPyV DVGs were derived from BKPyV genotypes Ia, Ib-1, and Ic. The presence of DVGs was associated with specimens containing higher viral loads but never reached clonality, consistent with a model of parasitized replication. These DVGs persisted during clinical infection as evidenced in two separate pairs of samples containing BK virus collected from the same individual up to 302 days apart. In a separate individual, we observed the generation of DVGs after a 57.5-fold increase in viral load. In summary, by extending the presence of DVGs in clinical specimens to DNA viruses, we demonstrate the ubiquity of DVGs in clinical virology. IMPORTANCE Defective viral genomes (DVGs) can have a significant impact on the production of infectious virus particles. DVGs have only been identified in cultured viruses passaged at high multiplicities of infection and RNA viruses collected from clinical specimens – no DNA virus in the wild has been shown to contain DVGs. Here, we identified BK and JC polyomavirus DVGs in clinical urine specimens and demonstrated that these DVGs are more frequently identified in samples with higher viral loads. The strains containing DVGs had rearrangements throughout their genomes with the majority affecting genes required for viral replication. Longitudinal analysis showed these DVGs can persist during an infection, but do not reach clonality within the chronically infected host. Our identification of polyomavirus DVGs suggests these parasitic sequences exist across the many classes of viruses capable of causing human disease.

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Section: Methodsmentioning

confidence: 99%

In Vivo Generation of BK and JC Polyomavirus Defective Viral Genomes in Human Urine Samples Associated with Higher Viral Loads

Addetia

Phung

Bradley

et al. 2021

J Virol

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“…The BKPyV NCCR is hypervariable, and detection of the rearranged (rr) strains (i.e., Dunlop), correlates with BKPyV diseases including polyomavirus-associated nephropathy [ 90 , 91 , 92 , 93 ]. Further, the BKPyV NCCR contains binding sites for TFs: AP-1, NF-1, NF-kB, Sp1, and Spi-B [ 89 , 94 , 95 , 96 ], which are also found in the JCPyV NCCR. Additionally, Sp1 and Spi-B sites are present in all known human polyomaviruses [ 97 ].…”

Section: Discussionmentioning

confidence: 99%

Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes

Wilczek

Pike

Craig

et al. 2022

IJMS

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JC polyomavirus (JCPyV) is the causative agent of the fatal, incurable, neurological disease, progressive multifocal leukoencephalopathy (PML). The virus is present in most of the adult population as a persistent, asymptotic infection in the kidneys. During immunosuppression, JCPyV reactivates and invades the central nervous system. A main predictor of disease outcome is determined by mutations within the hypervariable region of the viral genome. In patients with PML, JCPyV undergoes genetic rearrangements in the noncoding control region (NCCR). The outcome of these rearrangements influences transcription factor binding to the NCCR, orchestrating viral gene transcription. This study examines 989 NCCR sequences from patient isolates deposited in GenBank to determine the frequency of mutations based on patient isolation site and disease status. The transcription factor binding sites (TFBS) were also analyzed to understand how these rearrangements could influence viral transcription. It was determined that the number of TFBS was significantly higher in PML samples compared to non-PML samples. Additionally, TFBS that could promote JCPyV infection were more prevalent in samples isolated from the cerebrospinal fluid compared to other locations. Collectively, this research describes the extent of mutations in the NCCR that alter TFBS and how they correlate with disease outcome.

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“…Viral read k-mers were cross-compared against samples for uniqueness to identify index hopping or potential contamination between samples. Rearrangements in the BKPyV regulatory region were analyzed and annotated using BKTyper (37). Oncovirus Tools (github.com/gstarrett/oncovirus_tools) was used to isolate and assemble integration junctions (38, 39).…”

Section: Methodsmentioning

confidence: 99%

Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients

Starrett

Golubeva

et al. 2021

Preprint

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A small percentage of bladder cancers in the general population have been found to harbor polyomaviruses and papillomaviruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer, have been reported to harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from any potential oncovirus, we performed whole genome sequencing and transcriptomic sequencing on bladder cancer specimens from 43 transplant patients. Roughly a third of the tumors from this patient population contained viral sequences, among which the most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). BKPyV presence was validated by Large T antigen staining and revealed heterogeneous staining patterns between cases ranging from less than one percent to 100% of tumor tissue staining positive. In most cases of BKPyV-positive tumors, the viral genome was integrated into the host chromosome consistent with microhomology-mediated end joining and, in some cases, resulting in focal amplifications of the tumor genome. In BKPyV-positive tumors, significant changes in the expression of E2F- and DREAM-regulated genes amongst others were also observed consistent with the depletion of RB-family members by BKPyV Large T antigen in the tumors. We identified four mutation signatures in our cases with APOBEC3 and SBS5 mutations being the most abundant. We also identified a widespread mutation signature most similar to that caused by the antiviral, ganciclovir, and several cases harbored a high mutation burden associated with aristolochic acid, a nephrotoxic compound found in some herbal medicines. The results indicate that viruses may play a causal role in the development of bladder cancer among immunosuppressed individuals.

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BKTyper: Free Online Tool for Polyoma BK Virus VP1 and NCCR Typing

Cited by 10 publications

References 35 publications

In Vivo Generation of BK and JC Polyomavirus Defective Viral Genomes in Human Urine Samples Associated with Higher Viral Loads

In Vivo Generation of BK and JC Polyomavirus Defective Viral Genomes in Human Urine Samples Associated with Higher Viral Loads

Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes

Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients

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