1. Persistent infection of the central nervous system by Theiler's virus
Theiler’s murine encephalomyelitis virus (TMEV or Theiler’s virus) is a murine picornavirus showing a striking ability to persist in the central nervous system of the host in spite of a specific cellular and humoral immune response. Persistence of the virus is associated with a strong inflammatory response and with lesions of primary demyelination reminiscent of those found in human multiple sclerosis (Brahic et al., Annu rev. Microbiol., 2005). Our work aims at understanding how a virus can persist in the central nervous system (CNS) of an immunocompetent host, thus evading the immune response.
We currently analyze the function of two viral proteins, namely L and L*, that are critical for persistence of the virus in the central nervous system though they are not required for replication of the virus in cell culture. Hence, these proteins are believed to interact with host factors in vivo and to counteract the host immune defenses.
L Protein: The leader (L) protein encoded by Theiler's virus is a 76 amino acid-long peptide containing a zinc-binding motif. In spite of its small size, this protein exerts several important activities. It inhibits the production of IFN-α/β by infected cells (van Pesch et al., J. Virol. 2001) and affects the nucleo-cytoplasmic trafficking of host proteins (Delhaye et al., J. Virol. 2004). A structure-function analysis of the L protein is underway to identify the functional motifs of the L protein and to test how much IFN production inhibition and nucleo-cytoplamsic traffic perturbation are related functions.
L* Protein: Protein L* of Theiler's virus is unique among picornaviruses in that it is translated from an alternative open reading frame overlapping the ORF encoding the viral polyprotein. Translation of both the viral polyprotein and the L* protein depends on a Ribosome Internal Entry Site (IRES) located in the 5' non-coding region of the genome.
We showed that the L* protein is required for long term persistence of the virus in the central nervous system. In vitro, L* facilitates the infection of macrophages (van Eyll et al. J. Virol. 2000, 2002). Our recent data suggest that L* antagonizes a well-known pathway of the IFN response. Analysis of the mechanisms of this inhibition is underway.
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