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

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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. Strains of the mouse polyoma virus adapted to growth in cell culture vary greatly in their abilities to cause disease. Pathogenicities of these laboratory strains range from “attenuated” to “highly virulent” when tested in animals. The biological differences are based in large part on variations in the outer capsid protein, which dictate the manner in which the virus recognizes and binds to cell receptors. In contrast, strains of virus newly isolated from wild mice are uniform in their receptor-binding properties. Naturally occurring strains avoid binding to pseudoreceptors, which would severely limit their ability to spread. At the same time, their avidity of binding to true receptors is sufficiently strong to avoid rapid dissociation and potentially lethal spread. They are therefore neither attenuated nor virulent. The new isolates do, however, retain the ability to induce a broad spectrum of tumors in the laboratory. These findings emphasize the importance of neonatal and maternal immune responses in allowing a potentially highly oncogenic virus to disseminate without causing disease.