Genetic and structural analysis of a virulence determinant in polyomavirus VP1

Abstract

The LID strain of polyomavirus differs from other laboratory strains in causing a rapidly lethal infection of newborn C3H/Bi mice. This virulent behavior of LID was attenuated by dilution, yet at sublethal doses LID was able to induce tumors at a high frequency, like its parent virus PTA. By constructing and assaying LID-PTA recombinant viruses and by DNA sequencing, the determinant of virulence in LID was mapped to the major viral capsid protein, VP1. The VP1s of LID and PTA differed at two positions: at 185, LID has phenylalanine and PTA has tyrosine, and at 296, LID has alanine and PTA has valine. Results obtained with viruses constructed by site-directed mutagenesis showed that alanine at position 296 is sufficient to confer a fully virulent phenotype regardless of which amino acid is at position 185. However, with valine at position 296, an effect of phenylalanine at position 185 is apparent, as this virus possesses an intermediate level of virulence. A crystal structure of polyomavirus complexed with 3-sialyl lactose previously indicated van der Waals contacts between the side chain of valine 296 and the sialic acid ring (T. Stehle, Y. Yan, T. L. Benjamin, and S. C. Harrison, Nature [London] 369:160-163, 1994). When this interaction was modeled with alanine, these contacts were greatly reduced. Direct confirmation that the substitutions in VP1 affected receptor binding was obtained by studying virus hemagglutination behavior. The ensemble of results are discussed in terms of the idea that a lower affinity of the virus for its receptor can result in more rapid spread and increased pathogenicity.

Mutations in the GM1 Binding Site of Simian Virus 40 VP1 Alter Receptor Usage and Cell Tropism

“…In addition to the effects of mutations in the receptor binding region of mPyV VP1 noted above (3,4), similar mutations have previously been implicated in changes in human polyomavirus receptor usage and pathogenicity. BKV isolated from patients with viremia and nephropathy had a high frequency of substitutions in the BC loop region (27).…”

“…By preventing recognition of branched-chain oligosaccharide pseudoreceptors without affecting binding to the functional straight-chain receptor, the G91E substitution in mPyV VP1 increases virus spread and broadens virus tropism in the murine host, which results in increased pathogenicity (4,14). Moreover, the V296A substitution, which is found in the LID laboratory strain of mPyV that also contains the G91E mutation, further increases virus spread and expands tropism by reducing avidity for the functional receptor, resulting in an extremely virulent virus (3). In contrast, the A70L/F75L/H129Q substitutions in SV40 VP1 appear to alter cell tropism by reducing affinity for the functional GM1 receptor and by allowing recognition of a new receptor.…”

The Murine Coronavirus Hemagglutinin-esterase Receptor-binding Site: A Major Shift in Ligand Specificity through Modest Changes in Architecture

“…Viruses have evolved to selectively use particular Sia variants and their attachment proteins are high-specificity sialolectins, the binding of which might depend on the identity of the penultimate residue in the sugar chain, the type of glycosidic linkage and/or the presence or absence of substitutions [5][6][7][8][9]. Ultimately, this preference in Sia receptor usage affects host-, organ-, and cell-tropism [10][11][12][13][14], the course and outcome of infection [15][16][17][18] as well as the efficacy of intra-and cross-species transmission [14,19], all to extents not yet fully appreciated.…”

VP‐1 quasispecies in human infection with polyomavirus BK

“…Less likely possibilities include replicative fitness, immune escape or better adaptability to the metabolic milieu of the cell. BC loop mutations are known to enhance the plaque forming ability of mouse polyomavirus [Bauer et al, 1995;Freund et al, 1991]. Recently, loop specific polymorphisms in polyomavirus JC virus have been associated with favorable prognosis in patients with progressive multifocal encephalopathy [Delbue et al, 2009].…”