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Mutation in Loop I of VP1 of Theiler's Virus Delays Viral RNA Release into Cells and Enhances Antibody-mediated Neutralization: a Mechanism for the Failure of Persistence by the Mutant Virus

Overview
Journal J Neurovirol
Publisher Springer
Specialties Microbiology
Neurology
Date 2002 Apr 6
PMID 11935462
Citations 5
Authors
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Abstract

The DA strain of Theiler's murine encephalomyelitis viruses (TMEV) causes a central nervous system (CNS) demyelinating disease with viral persistence despite the presence of high serum anti-TMEV antibody titers. The DA virus mutant, T81D, was created to have a mutation at position 81 in loop I of VP1, close to the putative virus receptor binding site. T81D showed slower replication in vitro and in vivo. T81D-infected mice developed anti-TMEV antibody responses with no virus persistence. We tested whether the differences between the viruses were due to alteration in virus-cell interactions, or in the resistance to neutralization by anti-TMEV antibody. Using radiolabeled viruses, we found no difference in binding to permissive cell lines between the mutant and wild-type viruses. In a semipermissive cell line, DA virus bound more efficiently than T81D. During the uncoating step, both viruses decapsidated without the production of stable intermediates and 80% of viruses were eluted or decapsidated after 45 minutes. At the final step of uncoating, however, T81D showed a slower rate of RNA release than DA virus into cells using a photoinactivation assay. Anti-TMEV monoclonal and polyclonal antibodies neutralized T81D virus more efficiently than DA virus in suspension. Further, these anti-TMEV antibodies were able to neutralize viruses that had already attached to cells but not internalized (postadsorption neutralization [PAN]). However, DA virus showed significant resistance to PAN after cells were incubated at 37 degrees C compared with T81D-infected cells. The development of resistance to PAN appeared to correlate with the rate of RNA release from virions into cells. In T81D virus infection, the slow RNA release and high susceptibility to neutralization by antibodies would result in a failure to establish virus persistence in vivo. Conversely, rapid RNA release and resistance to neutralization could favor virus persistence in DA virus infection.

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