The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production

Theiler's virus is a picornavirus responsible for a persistent infection of the central nervous system of the mouse, leading to a chronic demyelinatin g disease considered to be a model for multiple sclerosis. The leader (L) p rotein encoded by Theiler's virus is a 76-amino-acid-long peptide containin g a zinc-binding motif. This motif is conserved in the L proteins of all ca rdioviruses, including encephalomyocarditis virus. The L protein of Theiler 's virus was suggested to interfere with the alpha/beta interferon (IFN-alp ha/beta) response (W.-P. Kong, G. D. Ghadge, and R. P. Roos, Proc. Nad. Aca d. Sci. USA 91:1796-1800, 1994). We show that expression of the L protein i ndeed inhibits the production of alpha/beta interferon by infected L929 cel ls. The L protein specifically inhibits the transcription of the IFN-alpha4 and IFN-beta genes, which are known to be activated early in response to v iral infection. Mutation of the zinc finger was sufficient to block the ant i-interferon activity, outlining the importance of this motif in the L prot ein function. In agreement with the anti-interferon role of the L protein, a virus bearing a mutation in the zinc-binding motif was dramatically impai red in its ability to persist in the central nervous system of SJL/J mice.