Receptor-Binding and Oncogenic Properties of Polyoma Viruses Isolated from Feral Mice

Abstract

Laboratory strains of the mouse polyoma virus differ markedly in their abilities to replicate and induce tumors in newborn mice. Major determinants of pathogenicity lie in the sialic binding pocket of the major capsid protein Vp1 and dictate receptor-binding properties of the virus. Substitutions at two sites in Vp1 define three prototype strains, which vary greatly in pathogenicity. These strains replicate in a limited fashion and induce few or no tumors, cause a disseminated infection leading to the development of multiple solid tumors, or replicate and spread acutely causing early death. This investigation was undertaken to determine the Vp1 type(s) of new virus isolates from naturally infected mice. Compared with laboratory strains, truly wild-type viruses are constrained with respect to their selectivity and avidity of binding to cell receptors. Fifteen of 15 new isolates carried the Vp1 type identical to that of highly tumorigenic laboratory strains. Upon injection into newborn laboratory mice, the new isolates induced a broad spectrum of tumors, including ones of epithelial as well as mesenchymal origin. Though invariant in their Vp1 coding sequences, these isolates showed considerable variation in their regulatory sequences. The common Vp1 type has two essential features: 1) failure to recognize “pseudoreceptors” with branched chain sialic acids binding to which would attenuate virus spread, and 2) maintenance of a hydrophobic contact with true receptors bearing a single sialic acid, which retards virus spread and avoids acute and potentially lethal infection of the host. Conservation of these receptor-binding properties under natural selection preserves the oncogenic potential of the virus. These findings emphasize the importance of immune protection of neonates under conditions of natural transmission.

Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

“…For example, influenza viruses have been shown to change their glycan usage in response to selective pressure from neutralizing antibodies, resulting in changes in tissue tropism and increased pathogenicity (Hensley et al, 2009; O’Donnell et al, 2012). The hypervirulent LID strain of mouse polyomavirus, which harbors a VP1 V296A mutation (homologous to the PML-associated S269F mutation in JCV) engages an altered spectrum of sialylated glycans, shows different tissue tropism, and is more rapidly lethal than wild-type mouse polyomavirus strains (Bauer et al, 1999; Carroll et al, 2007). Likewise, there is a link between sialylated glycan affinity and pathogenicity for parvoviruses, including canine parvovirus and minute virus of mouse (Huang et al, 2014).…”

Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

“…All MPyV isolates from feral mice have a glutamic acid at VP1 position 91 (11). From the perspective of virus-host coevolution, it is seemingly counterintuitive that mice in the wild harbor MPyV strains with a VP1 amino acid shared by highly tumorigenic laboratory strains.…”

“…An E at this position in VP1 leads to electrostatic repulsion of the (␣-2,6)-linked sialic acids, thereby preventing binding of such branched structures by LP strains; however, binding to gangliosides with sialic acid (␣-2,3)-linked to galactose is retained for virion uptake into an infectious pathway (9,10). Interestingly, MPyVs isolated from feral mice have exclusively E-91 VP1s, an unexpected finding given that such LP viruses are potentially more oncogenic than G-91 SP viruses (11).…”

Exposure to raccoon polyomavirus (RacPyV) in free-ranging North American raccoons (Procyon lotor)

“…Sequence variation between polyomavirus genotypes has been demonstrated to have effects on pathological outcomes 8–10 . For example, sequences in the noncoding region of the polyomavirus genome differ between tumor tissue and non-tumor tissues (sites of viral persistence) in mouse polyomavirus 11 and Merkel cell polyomavirus 12 , PyVs which infect mice and humans, respectively.…”

“…For example, sequences in the noncoding region of the polyomavirus genome differ between tumor tissue and non-tumor tissues (sites of viral persistence) in mouse polyomavirus 11 and Merkel cell polyomavirus 12 , PyVs which infect mice and humans, respectively. In addition, single nucleotide polymorphisms in the capsid protein gene VP1 resulting in single amino acid differences, have been associated with tumorigenic and nonpathogenic strains of mouse polyomavirus 10 . Comparing RacPyV isolates from different geographic locales, as well as isolates from tumor or non-tumor tissues could reveal specific sequence variations associated with tumor formation.…”