A determinant of polyomavirus virulence enhances virus growth in cells of renal origin

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We determined the DNA sequences of the noncoding regions of two polyomavirus strains that differ profoundly in their abilities to induce tumors in mice. Differences between strains were found, both on the late side of the replication origin in the region containing known enhancer elements and on the early side of the origin, affecting the number and location of large-T-antigen-binding sites. By constructing and analyzing recombinant viruses between these highand low-tumor strains, we attempted to localize determinants which affect the frequency and histotype of tumors. Seven recombinants were constructed and propagated in vitro, and the tumor profile of each was established by inoculation into newborn C3H mice. Recombinants containing noncoding sequences from the high-tumor strain and coding sequences from the low-tumor strain behaved like the latter, inducing tumors at a low frequency and strictly of mesenchymal origin. Reciprocal recombinants with noncoding sequences of the low-tumor strain linked to structural determinants from the high-tumor strain induced several types of epithelial tumors typical of the high-tumor strain but at reduced frequency, in addition to mesenchymal tumors. A high frequency and full diversity of epithelial tumors required, in addition to structural regions from the high-tumor strain, noncoding sequences on the early side of the origin also present in this strain. A high-tumor profile thus resulted from the combined effects of structural and regulatory determinants in the high-tumor strain, with the former affecting primarily the tissue tropism and the latter affecting the frequency of tumors. No differential effects of the enhancer regions from the late side of the origin in the two virus strains were seen in this study.

Section: Resultssupporting

confidence: 85%

Polyomavirus tumor induction in mice: influences of viral coding and noncoding sequences on tumor profiles

Freund

Mandel

Carmichael

et al. 1987

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“…Lytic lesions caused by LID were clearly more extensive and severe than those caused by PTA at each of the sites examined (Table 2). Similar findings with LID in the brain and kidney at 8 dpi have been reported previously (2). In the kidney, the major site of virus amplification, not only is the degree of infection with LID greater, but the pattern of infection within the organ differs as well.…”

Section: Virulent and Tumorigenic Behavior Of Molecularly Cloned Lidsupporting

confidence: 89%

“…The LID strain of polyomavirus has been shown to cause acute morbidity in a dose-dependent fashion when injected into newborn mice (2). To map the determinant of LID responsible for this effect, viral genomic DNA was first cloned and used to generate virus.…”

Section: Virulent and Tumorigenic Behavior Of Molecularly Cloned Lidmentioning

confidence: 99%

“…A laboratory isolate of polyomavirus known as LID is unique in that it causes a rapidly lethal infection of newborn mice. Originally derived from the high-tumor strain PTA by repeated passage in cultures of mouse embryo cells and in newborn mice (20,27), LID causes death within 1 to 2 weeks primarily from kidney failure and brain hemorrhages (2). The Kilham mouse virus is also lethal when injected into newborn mice, but it produces death due to interstitial pneumonia (16), and its genome is more similar to that of simian virus 40 than to that of the mouse polyomavirus of interest here (21).…”

mentioning

confidence: 99%

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Genetic and structural analysis of a virulence determinant in polyomavirus VP1

Bauer

Bronson

Fung

et al. 1995

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.

“…MA/MyJ mice are resistant to the virulent LID virus strain. LID is a virulent strain of polyomavirus which spreads rapidly in newborn mice, inducing widespread cytolytic damage, particularly in the kidney and brain (2,3). Newborn mice were inoculated intraperitoneally with 10 6 PFU of the LID strain, as previously described (2).…”

Section: Resultsmentioning

confidence: 99%

Radiation-Resistant and Radiation-Sensitive Forms of Host Resistance to Polyomavirus

Carroll

Fung

Bronson

et al. 1999

Newborn mice of several inbred strains develop few or no tumors following inoculation with highly tumorigenic strains of polyomavirus. Here we show that such resistant strains can be divided into two groups based on the responses of adult mice to radiation followed by virus inoculation. Most strains show a radiation-sensitive form of resistance (Rr-s) and develop tumors following radiation and virus challenge. This type of resistance has previously been recognized as immunological, based on T-cell responses against virus-encoded neoantigen(s) expressed in tumor cells. Other strains exhibit a radiation-resistant form of resistance (Rr-r) and fail to develop tumors when treated in the same manner. Three additional properties of Rr-r mice distinguish them from Rr-s mice: (i) survival of newborns following inoculation with a highly virulent and usually lethal strain of virus, (ii) resistance to virus spread in newborns inoculated with either tumorigenic or virulent virus strains, and (iii) dominant or semidominant transmission of resistance in crosses with a highly susceptible strain. The Rr-r phenotype reflects a constitutive nonimmunological type of resistance that is targeted to the virus and blocks its dissemination.