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In vivo generation of BK and JC polyomavirus defective viral genomes in human urine samples associated with higher viral loads

Amin Addetia, Quynh Phung, Benjamin T. Bradley, Michelle Lin, Haiying Zhu, Hong Xie, Meei-Li Huang, View ORCID ProfileAlexander L. Greninger
doi: https://doi.org/10.1101/2021.02.12.431053
Amin Addetia
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
2Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA
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Quynh Phung
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
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Benjamin T. Bradley
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
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Michelle Lin
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
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Haiying Zhu
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
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Hong Xie
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
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Meei-Li Huang
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
2Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA
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Alexander L. Greninger
1Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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  • ORCID record for Alexander L. Greninger
  • For correspondence: agrening@uw.edu
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ABSTRACT

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 universally derived from type I subtype BKPyV. 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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 13, 2021.
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In vivo generation of BK and JC polyomavirus defective viral genomes in human urine samples associated with higher viral loads
Amin Addetia, Quynh Phung, Benjamin T. Bradley, Michelle Lin, Haiying Zhu, Hong Xie, Meei-Li Huang, Alexander L. Greninger
bioRxiv 2021.02.12.431053; doi: https://doi.org/10.1101/2021.02.12.431053
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In vivo generation of BK and JC polyomavirus defective viral genomes in human urine samples associated with higher viral loads
Amin Addetia, Quynh Phung, Benjamin T. Bradley, Michelle Lin, Haiying Zhu, Hong Xie, Meei-Li Huang, Alexander L. Greninger
bioRxiv 2021.02.12.431053; doi: https://doi.org/10.1101/2021.02.12.431053

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