Molecular characterization of a nondemyelinating variant of Daniel's strain of Theiler's virus isolated from a persistently infected glioma cell line

Xiaoqi Lin, Shigeru Sato, Amy K. Patick, Larry R Pease, Raymond P. Roos, Moses Rodriguez

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Wild-type Daniel's strain of Theiler's virus (wt-DA) induces a chronic demyelination in susceptible mice which is similar to multiple sclerosis. A variant of wt-DA (designated DA-P12) generated during the 12th passage of persistent infection of a G26-20 glioma cell line failed to persist and induce demyelination in SJL/J mice. To identify the determinants responsible for this change in phenotype, we sequenced the capsid coding sequence (nucleotides [nt] 2991 to 3994) and found three mutations in VP1: residues 99 (Gly to Ser), 100 (Gly to Asp), and 103 (Asn to Lys). To study the role of these mutations in neurovirulence and demyelination, we prepared a recombinant virus, DAP-1C-2A/DA, with replacement of wt-DA nt 2991 to 3994 with the corresponding region of DA-P12, and viruses with individual point mutations at VP1 residues 99(Ser), 100(Asp), and 103(Lys). DAP-1C-2A/DA and viruses with a mutation at VP1 residue 99 or 100 (but not 103) completely attenuated the ability of wt-DA to induce demyelination. Failure to induce demyelination was not due to a general failure in growth, since DA-P12 and other mutant viruses lysed L-2 cells in vitro as effectively as wt-DA. The change in disease phenotype was independent of the specific B- or T-cell immune recognition because a decrease in the neurovirulence of mutant viruses was observed in neonatal mice and immune-deficient RAG1 -/- mice. This difference in neurovirulence is not the complete explanation for the failure of DA-P12 to demyelinate, since virus with a mutation at residue 103(Lys) had decreased neurovirulence but did induce demyelination. Therefore, point mutation at VP1 residue 99 or 100 altered the ability of wt-DA to demyelinate, perhaps related to a disruption in interaction between virus and receptor on certain neural cells.

Original languageEnglish (US)
Pages (from-to)1262-1269
Number of pages8
JournalJournal of Virology
Volume72
Issue number2
StatePublished - Feb 1998

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Theilovirus
Demyelinating Diseases
Glioma
cell lines
Viruses
Cell Line
viruses
Mutation
Viperidae
mutation
Point Mutation
point mutation
Virus Receptors
Phenotype
mice
Capsid
phenotype
mutants
Multiple Sclerosis
capsid

ASJC Scopus subject areas

  • Immunology

Cite this

Molecular characterization of a nondemyelinating variant of Daniel's strain of Theiler's virus isolated from a persistently infected glioma cell line. / Lin, Xiaoqi; Sato, Shigeru; Patick, Amy K.; Pease, Larry R; Roos, Raymond P.; Rodriguez, Moses.

In: Journal of Virology, Vol. 72, No. 2, 02.1998, p. 1262-1269.

Research output: Contribution to journalArticle

Lin, Xiaoqi ; Sato, Shigeru ; Patick, Amy K. ; Pease, Larry R ; Roos, Raymond P. ; Rodriguez, Moses. / Molecular characterization of a nondemyelinating variant of Daniel's strain of Theiler's virus isolated from a persistently infected glioma cell line. In: Journal of Virology. 1998 ; Vol. 72, No. 2. pp. 1262-1269.
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abstract = "Wild-type Daniel's strain of Theiler's virus (wt-DA) induces a chronic demyelination in susceptible mice which is similar to multiple sclerosis. A variant of wt-DA (designated DA-P12) generated during the 12th passage of persistent infection of a G26-20 glioma cell line failed to persist and induce demyelination in SJL/J mice. To identify the determinants responsible for this change in phenotype, we sequenced the capsid coding sequence (nucleotides [nt] 2991 to 3994) and found three mutations in VP1: residues 99 (Gly to Ser), 100 (Gly to Asp), and 103 (Asn to Lys). To study the role of these mutations in neurovirulence and demyelination, we prepared a recombinant virus, DAP-1C-2A/DA, with replacement of wt-DA nt 2991 to 3994 with the corresponding region of DA-P12, and viruses with individual point mutations at VP1 residues 99(Ser), 100(Asp), and 103(Lys). DAP-1C-2A/DA and viruses with a mutation at VP1 residue 99 or 100 (but not 103) completely attenuated the ability of wt-DA to induce demyelination. Failure to induce demyelination was not due to a general failure in growth, since DA-P12 and other mutant viruses lysed L-2 cells in vitro as effectively as wt-DA. The change in disease phenotype was independent of the specific B- or T-cell immune recognition because a decrease in the neurovirulence of mutant viruses was observed in neonatal mice and immune-deficient RAG1 -/- mice. This difference in neurovirulence is not the complete explanation for the failure of DA-P12 to demyelinate, since virus with a mutation at residue 103(Lys) had decreased neurovirulence but did induce demyelination. Therefore, point mutation at VP1 residue 99 or 100 altered the ability of wt-DA to demyelinate, perhaps related to a disruption in interaction between virus and receptor on certain neural cells.",
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