International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G15. The H-2D Class I Gene Alone Explains the Effects of Tmevp1, the Locus of Susceptibility to Theiler's Virus Persistent Infection Present in the H-2 Region

Stephanie Aubagnac, Ariele Azoulay-Cayla, Sven Dethlefs, Beatrice Perarnau*, Francois Lemonnier*, Michel Brahic, Jean-Francois Bureau
Unite des Virus Lents, CNRS URA 1930,
* Unite d'Immunite Cellulaire Antivirale, Institut Pasteur, 75724 Paris Cedex 15, France

The persistent and demyelinating infection by Theiler's virus is a model for multiple sclerosis. A major locus of susceptibility to the persistence of Theiler's virus (Tmevp1) has been mapped to the H-2D region. The b haplotype confers resistance, the q haplotype confers a high level of susceptibility and d, k and s haplotypes are associated with an intermediate level of susceptibility. The resistant b haplotype is dominant over all the others. The SJL/J strain is an exception, being more susceptible to persistent infection than predicted by its H-2s haplotype. This has been ascribed to the existence of non H-2 susceptibility genes. Strains of intermediate susceptibility, such as the B10.S strain (H-2s), are infected at low level but their F1 cross with the SJL/J strain are highly susceptible. Results from different groups demonstrated that the H-2D gene controls viral persistence and/or demyelination.

We now report, using three different approaches, that all the properties of the Tmevp1 locus can be explained by the effect on viral persistence of an H-2 class I gene. We showed that mice knock out for the H-2Db gene become susceptible to viral persistence, although mice knock out for the H-2Kb gene remain resistant. Conversely, we showed that susceptible FVB (H-2q) mice transgenic for the H-2Db gene become more resistant than FVB mice transgenic for the H-2Kb gene. These results confirmed that the H-2D gene, and not the H-2K gene, confers resistance to viral persistence. We also showed that susceptible SJL/J mice knock out for the ß2m gene are more susceptible than the SJL/J parent. Interestingly, SJL/J mice heterozygous for the ß2m knock out have an intermediate phenotype. These results showed that mice with an haplotype associated with intermediate susceptibility (H-2s) also control the level of viral persistence via class I genes. Taken together, our results show that the characteristics of Tmevp1 can be explained by a single class I gene (H-2D). This is in contrast to what as been shown for the locus of susceptibility to experimental autoimmune encephalomyelitis located in the H-2 region, which is multigenic.

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