A Determinant for Central Nervous System Persistence Localized in the Capsid of Theiler’s Murine Encephalomyelitis Virus by Using Recombinant Viruses

Abstract

The demyelinating process in Theiler’s murine encephalomyelitis virus (TMEV) infection in mice requires virus persistence in the central nervous system. Using recombinant TMEV assembled between the virulent GDVII and less virulent BeAn virus cDNAs, we now provide additional evidence supporting the localization of a persistence determinant to the leader P1 (capsid) sequences. Further, recombinant viruses in which BeAn sequences progressively replaced those of GDVII within the capsid starting at the leader NH2 terminus suggest that a conformational determinant requiring homologous sequences in both the VP2 puff and VP1 loop regions, which are in close contact on the virion surface, might underlie persistence.

Amino Acid Substitutions in VP2 Residues Contacting Sialic Acid in Low-Neurovirulence BeAn Virus Dramatically Reduce Viral Binding and Spread of Infection

“…Since these four viral residues are conserved in all TMEV (two high-and six low-neurovirulence capsid sequences are known) and the largest difference in root-mean-square deviation between the C␣ coordinates of viruses of the two neurovirulence groups lies in VP2 puff B (25), the capsid conformation of this region may be responsible for sialic acid binding. These data are also consistent with viral genetic studies that suggest the conformational nature of a TMEV persistence determinant involving the two sets of VP1 and VP2 surface loops that interact on the virion surface (1).…”

“…Genetic analyses of recombinant TMEV have mapped a major element for persistence to the sequences encoding the capsid proteins (8,23,28). In addition, studies of recombinant viruses in which the capsid sequences of the lowneurovirulence BeAn strain progressively replaced those of the high-neurovirulence GDVII virus starting at the leader N terminus suggest that a conformational determinant involving homologous BeAn sequences in the VP2 puff and VP1 loops is required for persistence (1). The mapping of a genetic element for persistence to the capsid suggests that a virus-receptor interaction(s) underlies TMEV persistence.…”

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).…”

“…VOL. 17,2004 TMEV-INDUCED DEMYELINATING DISEASE AND MS 177 are in close contact on the virion surface (3,252,477). These residues, located around the edge of the "pit," may be in close proximity to a putative receptor-binding site (47).…”

“…These residues, located around the edge of the "pit," may be in close proximity to a putative receptor-binding site (47). However, conflicting results have been obtained about whether these determinants for persistence and demyelination can be contributed only by the DA and BeAn strains (60,127,280,392) or whether these determinants are also present within the capsid of GDVII virus (3,127,392). In general, a chimeric GDVII virus, whose capsid had been replaced by that of the DA or the BeAn strain, was attenuated whereas a recombinant DA or BeAn virus with a GDVII capsid was virulent.…”