Novel Polyomavirus associated with Brain Tumors in Free-Ranging Raccoons, Western United States

Cruz, Florante N. Dela; Giannitti, Federico; Li, Linlin; Woods, Leslie W.; Valle, Luis Del; Delwart, Eric; Pesavento, Patricia A.

doi:10.3201/eid1901.121078

Cited by 51 publications

(46 citation statements)

References 29 publications

(34 reference statements)

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“…Quality reads from the two normal olfactory bulb tissues were aligned to RacPyV strain R45 (GenBank accession no. JQ178241.1) (9).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, a robust collection of scientific evidence is needed to support the classification of RacPyV as a causative agent in raccoon neuroglial tumors. This is especially critical because RacPyV exists as an episome in raccoon brain tumors, whereas MCPyV is clonally integrated in MCC (9,12). As a minimal criterion for causality, regardless of its episomal state, we predict that the RacPyV genome and TAg transcription are consistently present in the tumor cell population.…”

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confidence: 93%

“…This is now considered the first example of cancer attributed to naturally occurring PyV infection in humans (7,8). In 2010, raccoon polyomavirus (RacPyV) was identified in neuroglial olfactory tract tumors of free-ranging raccoons (9). To date, 17 raccoon tumors, all of which harbor abundant viral genome, have been collected from the western United States.…”

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confidence: 99%

“…Like other PyVs, RacPyV has a circular double-stranded DNA genome of 5 kb with a noncoding regulatory region (NCRR) dividing the genome into the alternatively spliced early tumor antigen (TAg; nonstructural) region and the late capsid (VP; structural) region (9). RacPyV is closely related to MCPyV at both the genome and protein levels, and they both fall within a monophyletic clade of viruses that some have called almipolyomaviruses, which encode either an overprinting "ALTO" protein or a similarly overprinted middle tumor antigen (MT) protein (10).…”

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confidence: 99%

“…Several known oncogenic domains of PyV LT (a DnaJ domain and a retinoblastoma [pRB]-binding motif) and sT (protein phosphatase 2A [PP2A] binding motifs) are present as shown by sequence analysis (9). SV40 LT and sT, along with constitutive overexpression of human telomerase and the H-ras oncogene, are sufficient for complete primary cell transformation in vitro (11).…”

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confidence: 99%

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The Raccoon Polyomavirus Genome and Tumor Antigen Transcription Are Stable and Abundant in Neuroglial Tumors

Brostoff

Cruz

Church

et al. 2014

J Virol

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Raccoon polyomavirus (RacPyV) is associated with 100% of neuroglial tumors in free-ranging raccoons. Other tumor-associated polyomaviruses (PyVs), including simian virus 40 (SV40), murine PyV, and Merkel cell PyV, are found integrated in the host genome in neoplastic cells, where they constitutively express splice variants of the tumor antigen (TAg) gene. We have previously reported that RacPyV exists only as an episome (nonintegrated) in neuroglial tumors. Here, we have investigated TAg transcription in primary tumor tissue by transcriptome analysis, and we identified the alternatively spliced TAg transcripts for RacPyV. We also determined that TAg was highly transcribed relative to host cellular genes. We further colocalized TAg DNA and mRNA by in situ hybridization and found that the majority of tumor cells showed positive staining. Lastly, we examined the stability of the viral genome and TAg transcription by quantitative reverse transcriptase PCR in cultured tumor cells in vitro and in a mouse xenograft model. When tumor cells were cultured in vitro, TAg transcription increased nearly 2 log-fold over that of parental tumor tissue by passage 17. Both episomal viral genome and TAg transcription were faithfully maintained in culture and in tumors arising from xenotransplantation of cultured cells in mice. This study represents a minimal criterion for RacPyV's association with neuroglial tumors and a novel mechanism of stability for a polyomavirus in cancer. IMPORTANCEThe natural cycle of polyomaviruses in mammals is to persist in the host without causing disease, but they can cause cancer in humans or in other animals. Because this is an unpredictable and rare event, the oncogenic potential of polyomavirus is primarily evaluated in laboratory animal models. Recently, raccoon polyomavirus (RacPyV) was identified in neuroglial tumors of freeranging raccoons. Viral copy number was consistently high in these tumors but was low or undetectable in nontumor tissue or in unaffected raccoons. Unlike other oncogenic polyomaviruses, RacPyV was episomal, not integrated, in these tumors. To determine the stability of the viral genome and sustained transcription of the oncogenic tumor antigen genes, we cultured primary raccoon tumor cells and passaged them in mice, confirming the nonintegrated state of the virus and the maintenance of viral gene transcription throughout. RacPyV provides a naturally occurring and tractable model for a novel mechanism of polyomavirus-mediated oncogenesis.

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“…Quality reads from the two normal olfactory bulb tissues were aligned to RacPyV strain R45 (GenBank accession no. JQ178241.1) (9).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Raccoon Polyomavirus Genome and Tumor Antigen Transcription Are Stable and Abundant in Neuroglial Tumors

Brostoff

Cruz

Church

et al. 2014

J Virol

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2018

Veterinary Epidemiology

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Fecal, oral, blood and skin virome of laboratory rabbits

et al. 2020

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Here, we investigated the fecal, oral, blood, and skin virome of 10 laboratory rabbits using a viral metagenomic method. In the oral samples, we detected a novel polyomavirus (RabPyV), and phylogenetic analysis based on the large T antigen, VP1 and VP2 regions indicated that the novel strain might have undergone a recombination event. Recombination analysis based on related genomes confirmed that RabPyV is a multiple recombinant between rodent-like and avian-like polyomaviruses. In fecal samples, three partial or complete genome sequences of viruses belonging to the families Picobirnaviridae, Parvoviridae, Microviridae and Coronaviridae were characterized, and phylogenetic trees were constructed based on the predicted amino acid sequences of viral proteins. This study increases the amount of genetic information on viruses present in laboratory rabbits.

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Novel Polyomavirus associated with Brain Tumors in Free-Ranging Raccoons, Western United States

Cited by 51 publications

References 29 publications

The Raccoon Polyomavirus Genome and Tumor Antigen Transcription Are Stable and Abundant in Neuroglial Tumors

The Raccoon Polyomavirus Genome and Tumor Antigen Transcription Are Stable and Abundant in Neuroglial Tumors

References

Fecal, oral, blood and skin virome of laboratory rabbits

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