Viral Load Increases in SJL/J Mice Persistently Infected by Theiler's Virus after Inactivation of the 2m Gene (original) (raw)
H-2Db-/- Mice Are Susceptible to Persistent Infection by Theiler's Virus
Journal of Virology, 2000
gene and is associated with a potent antiviral cytotoxic T-lymphocyte (CTL) response. We used H-2 b mice in which the H-2D or the H-2K gene had been inactivated to dissect the respective roles of these genes in resistance. We report that H-2D ؊/؊ but not H-2K ؊/؊ mice were susceptible to persistent infection. Furthermore, whereas H-2K ؊/؊ mice mounted a vigorous virus-specific CTL response, similar to that of control C57BL/6 mice, the CTL response of H-2D ؊/؊ mice was nil or minimal. Using target cells transfected with the H-2D b or the H-2K b gene, we showed that the H-2K-restricted CTL response against the virus was minimal in H-2D ؊/؊ mice. These results demonstrate that the H-2D b and H-2K b genes play nonredundant roles in the resistance to this persistent infection.
Genetics, 1999
Theiler’s virus persistently infects the white matter of the spinal cord in susceptible strains of mice. This infection is associated with inflammation and primary demyelination and is studied as a model of multiple sclerosis. The H-2D gene is the major gene controlling viral persistence. However, the SJL/J strain is more susceptible than predicted by its H-2s haplotype. An (SJL/J × B10.S)F1 × B10.S backcross was analyzed, and one quantitative trait locus (QTL) was located in the telomeric region of chromosome 10 close to the Ifng locus. Another one was tentatively mapped to the telomeric region of chromosome 18, close to the Mbp locus. We now report the study of 14 congenic lines that carry different segments of these two chromosomes. Although the presence of a QTL on chromosome 18 was not confirmed, two loci controlling viral persistence were identified on chromosome 10 and named Tmevp2 and Tmevp3. Furthermore, the Ifng gene was excluded from the regions containing Tmevp2 and Tmev...
FVB mice trangenic for the H-2Db gene become resistant to persistent infection by Theiler’s virus
Journal of Virology
The DA strain of Theiler's virus causes a persistent infection of the white matter of the spinal cord with chronic inflammation and primary demyelination. Inbred strains of mice differ greatly in their susceptibility to this disease. It has been shown that both viral persistence and demyelination are controlled mainly by a gene located in the H-2D region. This raised the possibility that the H-2D gene itself controls viral persistence, which in turn determines demyelination. In the present work we introduced the H-2Db gene of resistant C57BL/6 mice into the genome of susceptible H-2q FVB mice and showed that the FVB mice become resistant to persistence of the infection and did not develop inflammatory lesions.
FVB mice transgenic for the H-2Db gene become resistant to persistent infection by Theiler's virus
Journal of Virology, 1994
The DA strain of Theiler's virus causes a persistent infection of the white matter of the spinal cord with chronic inflammation and primary demyelination. Inbred strains of mice differ greatly in their susceptibility to this disease. It has been shown that both viral persistence and demyelination are controlled mainly by a gene located in the H-2D region. This raised the possibility that the H-2D gene itself controls viral persistence, which in turn determines demyelination. In the present work we introduced the H-2Db gene of resistant C57BL/6 mice into the genome of susceptible H-2q FVB mice and showed that the FVB mice become resistant to persistence of the infection and did not develop inflammatory lesions.
Virology, 1995
Resistance to Theiler's virus-induced demyelination maps genetically to the MHC class I D region and is associated with up-regulation of class I products and the presence of MHC-restricted virus-specific cytotoxic CD8 / T cells in the CNS. To determine the targets of the cytotoxic response, transfected C57SV (K b , D b) cells expressing LP (including the leader peptide, VP4, VP2, and VP3 coding sequences), VP4 (including the leader peptide and VP4), VP2, VP3, VP1, or RP (including P2 and P3) were generated. CNS-infiltrating lymphocytes obtained from virus-infected B10, B10.K (K k , D k), B10.RBF (K b , D f), B10.RFB3 (K f , D b), and B10.RBQ (K b , D q) mice were used as effectors. Specific cytotoxicity to the capsid proteins encoded in the LP construct, VP2 and VP1, was demonstrated to be H-2D b region restricted and was mediated by CD8 / T cells. No K b-restricted virus-specific cytotoxicity response was observed. No specific cytotoxic response against RP-encoded proteins was observed in the CNS of B10 mice. Therefore, both VP1 and VP2 are targets for an H-2D-restricted cytotoxic immune response against Theiler's virus infection in the CNS of infected resistant B10 mice.
Journal of Virology, 1993
The highly structured 5' untranslated region (5' UTR) of Theiler's murine encephalomyelitis virus is involved in cap-independent translation of the viral RNA. Previously, we reported that the bicistronic mRNA chloramphenicol acetyltransferase-5' UTR-luciferase (Luc) efficiently expressed Luc both in a rabbit reticulocyte lysate and when transfected into BHK-21 cells. Insertion of 3 nucleotides at position 665 in the 5' UTR of this bicistronic mRNA resulted in greatly reduced Luc expression in BHK-21 cells but had little effect on expression of Luc in rabbit reticulocyte lysate. This mutation was also introduced into a virulent Theiler's murine encephalomyelitis virus chimera, Chi-VL. The kinetics of viral RNA and protein synthesis and virus production in BHK-21 cells were slower for the mutant chimera [Chi-VL(IN668)] than for Chi-VL; however, the final virus yields were comparable. Intracerebral inoculation of mice with the chimeras revealed that Chi-VL(IN668...
Journal of NeuroVirology, 2002
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 wildtype viruses. In a semipermissive cell line, DA virus bound more ef ciently 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 nal 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 ef ciently 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 signi cant resistance to PAN after cells were incubated at 37 ± 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. Journal of NeuroVirology (2002) 8, 100-110.
Infection of class II-deficient mice by the DA strain of Theiler's virus
Journal of virology, 1996
The DA strain of Theiler's virus causes, in susceptible strains of mice, a persistent infection of the white matter of the spinal cord accompanied by chronic inflammation and primary demyelination. In resistant strains, including all H-2b strains, mice clear the infection after 1 to 2 weeks. We inoculated RHAbetao/o mice, an H-2b strain which does not express class II molecules. We found that they are susceptible to persistent infection and that they develop foci of chronic inflammation with demyelination. However, these foci are smaller and contain fewer demyelinated axons than those observed in susceptible SJL/J or beta2m-/- mice.