A Theiler's virus alternatively initiated protein inhibits the generation of H-2K-restricted virus-specific cytotoxicity.
In susceptible mouse strains, the wild-type Daniel's (wt-DA) strain of Theiler's murine encephalomyelitis virus induces a persistent central nervous system (CNS) infection with chronic demyelination. The virus is cleared from resistant mice with no resulting demyelination. We characterized the role of the DA L* protein in late demyelination and persistent infection. The DA genome has two alternative reading frames, encoding the virus polyprotein and L*, respectively. The mutant virus DAL*-1 fails to synthesize L* and does not persist in the CNS of wt-DA-susceptible SJL/J or B10.S mice. Since class I-restricted cytotoxicity has been shown to determine resistance to virus persistence and demyelination in this model, virus-specific cytotoxicity in the CNS of DA-resistant (B6 or B10) and -susceptible (SJL/J and B10.S) mice during the acute stage of DA and DAL*-1 infection was characterized. Following intracerebral inoculation with DAL*-1, virus-specific Db- and Kb-restricted CTLs were demonstrated in the CNS of resistant B10 mice, whereas only Db-restricted CTL were found in wt-DA-inoculated mice. CTLs specific to wt-DA or DAL*-1 recognized class I-presented peptides from either of the viruses. Of particular interest, Ks-restricted virus-specific cytotoxicity-restricted CTLs were identified in the CNS of susceptible SJL/J (H-2s) and B10.S (H-2s) mice inoculated with DAL*-1. In contrast, no virus-specific CTLs were identified in the CNS of SJL/J and B10.S mice inoculated with wt-DA. We propose that L* inhibits the generation of H-2K-restricted virus-specific cytotoxicity in the CNS, permitting a persistent infection in susceptible strains, with subsequent inflammatory demyelination in the CNS similar to that in human multiple sclerosis.
Lin
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Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Roos
R P
RP
Pease
L R
LR
Wettstein
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P
Rodriguez
M
M
D017398:Alternative Splicing / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001927:Brain Diseases / Q000235:genetics / Q000276:immunology / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003711:Demyelinating Diseases / Q000276:immunology / Q000821:virology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007930:Leucine / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013122:Spinal Diseases / Q000235:genetics / Q000276:immunology / Q000821:virology; D013154:Spleen / Q000276:immunology / Q000821:virology; D017945:Theilovirus / Q000276:immunology* / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology*
D000914:Antibodies, Viral; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D014764:Viral Proteins; D007930:Leucine