A single amino acid change determines persistence of a chimeric Theiler's virus

Abstract

The DA strain of Theiler's virus persists in the central nervous system of mice and causes chronic inflammation and demyelination. On the other hand, the GDVII strain causes an acute encephalitis and does not persist in surviving animals. Series of recombinants between infectious cDNA clones of the genomes of DA and GDVII viruses have been constructed. The analysis of the phenotypes of the recombinant viruses has shown that determinants of persistence and demyelination are present in the capsid proteins of DA virus. Chimeric viruses constructed by the different research groups gave consistent results, with one exception. Chimeras GD1B-2A/DAFL3 and GDlB-2C/DAFL3, which contain part of capsid protein VP2, capsid proteins VP3 and VP1, and different portions of P2 of GDVII in a DA background, were able to persist and cause demyelination. Chimera R4, whose genetic map is identical to that of GD1B-2A/DAFL3, was not. After exchanging the viral chimeras between laboratories and verifying each other's observations, new chimeras were generated in order to explain this difference. Here we report that the discrepancy can be attributed to a single amino acid difference in the sequence of the capsid protein VP2 of the two parental DA strains. DAFL3 (University of Chicago) and the chimeras derived from it, GD1B-2A/DAFL3 and GDIB-2C/DAFL3, contain a Lys at position 141, while TMDA (Institut Pasteur) and R4, the chimera derived from it, contain an Asn in that position. This amino acid is located at the tip of the EF loop, on the rim of the depression spanning the twofold axis of the capsid. These results show that a single amino acid change can confer the ability to persist and demyelinate to a chimeric Theiler's virus, and they pinpoint a region of the viral capsid that is important for this phenotype.

Theiler's Virus Infection: a Model for Multiple Sclerosis

“…Chimeric viruses between GDVII (an extremely neurovirulent variant which induces only acute encephalitis and does not persist) and DA or BeAn (which cause persistence and demyelination) strains have been constructed. The major finding of these studies is that the viral capsid plays a major role in persistence (3,178,280,454). Within the capsid, several amino acids have been identified as being involved in establishing persistent infection (178,409,426,524).…”

“…The major finding of these studies is that the viral capsid plays a major role in persistence (3,178,280,454). Within the capsid, several amino acids have been identified as being involved in establishing persistent infection (178,409,426,524). It has been suggested that persistence depends on a conformational determinant within the capsid requiring homologous sequences in both the VP2 puff and VP1 loop, which Early acute disease Intense and multifocal mononuclear cell infiltrates in the grey matter of brain and spinal cord Attenuated grey matter disease, clinically inapparent 86,87,250,386,474 Late chronic demyelinating disease Clinically apparent at ϳ140-180 p.i.…”

“…Kang et al (191) reported that SJL mice infected with the BeAn strain of TMEV in fact generated a CD8 ϩ cytotoxic TMEV-specific T-cell response directed against the following three H-2K s -restricted viral epitopes: a dominant epitope (VP3 [159][160][161][162][163][164][165][166] ) and two subdominant epitopes (VP1 [11][12][13][14][15][16][17][18][19][20] and VP3 [173][174][175][176][177][178][179][180][181] ) of the BeAn virus capsid protein (191). The TMEV-BeAn strain is different from the TMEV DA strain, as discussed above (Table 1).…”

Intracerebral Inoculation of Mouse-Passaged Saffold Virus Type 3 Affects Cerebellar Development in Neonatal Mice

“…Mutations in the passaged strain affect interactions between residues at positions 62 and 160. The VP2 and VP3 proteins of Cardiovirus B species are known to form the pentamer lattice on the virion surface (33) and play critical roles in viral infection (41)(42)(43)(44). To address the structural impacts of the three mutations in the capsid proteins of the AM-5Cb strain, we constructed molecular models of the VP2 and VP3 proteins in the virion.…”

Borna Disease Virus and the Brain

“…Viral variants, even single amino acid substitutions, can exhibit remarkable differences in their expression pattern in cells and tissues of the infected host, that are associated with diverse disease phenotypes [98,210]. Similarly, genetic differences among individuals play a critical role in the outcome of a viral infection [32].…”