Downloaded from www.microbiologyresearch.org by IP: 23.22.24.125 On: Tue, 09 Feb 2016 17:39:23 Journal of General Virology (2001), 82, 1043–1047. Printed in Great Britain .......................................................................................................................................................................................................... SHORT COMMUNICATION Roles of the H-2D b and H-K b genes in resistance to persistent Theiler’s murine encephalomyelitis virus infection of the central nervous system Arie  le Azoulay-Cayla,† Sylvie Syan, Michel Brahic and Jean-François Bureau Unite  des Virus Lents, CNRS URA 1930, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France Theiler’s murine encephalomyelitis virus, a member of the Picornaviridae family, persists in the spinal cord of susceptible strains of mice. Resistant strains of mice, such as the H-2 b strain, clear the virus infection after an acute encephalomyelitis. The H- 2D locus, but not the H-2K locus, has a major effect on this resistance, although both loci code for MHC class I molecules with similar general properties. For the present work, we rendered susceptible H-2 q FVB/N mice transgenic for either the H-2D b gene, the H-2K b gene or a chimeric H-2D b /K b gene in which the exons encoding the peptide-binding groove of the H-2K b gene have been replaced by those of the H-2D b gene. Mice transgenic for either the H-2D b gene or the chimeric H-2D b /K b gene were significantly more resistant to persistent virus in- fection than mice transgenic for the H-2K b gene, suggesting that the difference in the effects of the H-2D b gene and the H-2K b gene are due to the nature of the peptides presented by these class I molecules. The DA strain of Theiler’s murine encephalomyelitis virus (TMEV), a member of the Picornaviridae family, is responsible for a biphasic disease of the murine CNS. The first phase is an acute encephalomyelitis, which takes place during the first 2 weeks after intracerebral inoculation. This is followed, only in genetically susceptible animals, by a persistent infection of the white matter of the spinal cord, resulting in inflammation and chronic primary demyelination. This natural disease is one of the best animal model systems available for multiple sclerosis (Dal Canto & Lipton, 1977 ; Author for correspondence : Michel Brahic. Fax 33 1 40 61 31 67. e-mail mbrahicpasteur.fr † Present address : Fe  de  ration de Neurologie, Ho  pital de la Salpe  trie  re, 75651 Paris Cedex 13, France. Monteyne et al., 1997). Susceptibility to the second phase of disease varies greatly among inbred strains of mice (Lipton & Dal Canto, 1979 ; Lipton & Melvold, 1984). Several genetic loci implicated in susceptibility to virus persistence, de- myelination and clinical disease have been identified (Brahic & Bureau, 1998). A locus with a major effect on demyelination was first located in the H-2D region of the MHC (Clatch et al., 1985; Lipton & Melvold, 1984; Rodriguez & David, 1985; Rodriguez et al., 1986). Resistance was dominant over susceptibility (Patick et al., 1990). Studying susceptibility to persistent TMEV infection in 17 inbred strains of mice, we later showed that the b haplotype was associated with resistance, the q haplotype was associated with full susceptibility, and the k, d, and s haplotypes were associated with intermediate susceptibility. The resistance that was brought by the b haplotype was dominant. The locus controlling virus per- sistence was mapped to the H-2D region of the MHC (Bureau et al., 1992). It is most likely that the H-2 loci that control the susceptibility to persistent TMEV infection and susceptibility to demyelination are the same (Bureau et al., 1992 ; Patick et al., 1990 ; Rodriguez et al., 1986). Several observations suggest that the susceptibility gene present in the H-2D region is an MHC class I H-2D gene (Azoulay-Cayla et al., 1994, 2000 ; Fiette et al., 1993 ; Lin et al., 1997 ; Pullen et al., 1993 ; Rodriguez et al., 1986, 1993). The role of the H-2D b gene in resistance was formally demonstrated by showing that (H-2 q ) FVBN mice, made transgenic for the H-2D b gene, are resistant to virus persistence (Azoulay-Cayla et al., 1994 ; Rodriguez & David, 1995) and that mutations in the H-2D b gene reduce or delay virus clearance (Lipton et al., 1995). The highly polymorphic exons 2 and 3 of class I genes code for the peptide-binding groove of the class I molecule. The polymorphism of this groove explains the large repertoire of peptides that can be presented to CD8 + T cells. The class I genes of the mouse are located in two sub-regions of the MHC, H-2K and H-2DL. To date, no difference in the ability to present peptides has been demonstrated between the families of H-2K and H-2DL proteins. In spite of this, resistance to both TMEV persistence and virus-induced demyelination is linked to the H-2D locus, and not to the H-2K locus, in strains 0001-7460  2001 SGM BAED