The CD4-mediated immune response is critical in determining the outcome of infection using Theiler's viruses with VP1 capsid protein point mutations.
Daniel's strain of Theiler's virus (DA) induces a chronic demyelinating disease in the central nervous system (CNS) of susceptible SJL mice, which serves as an excellent model of multiple sclerosis. We previously demonstrated that point mutations near a putative virus receptor-binding site [VP1 99 (Gly to Ser) or 100 (Gly to Asp)] totally attenuate the ability of DA to persist and induce demyelination in SJL mice. The current studies demonstrate that class II-restricted CD4(+) T cells play a major role in clearing VP1 mutant DA viruses from the CNS to prevent demyelination. Infection of SJL CD4((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100(Asp) resulted in virus persistence and prominent demyelination in the spinal cord. In contrast, infection of SJL CD8((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100 did not result in virus persistence or demyelination. In addition, no virus-specific cytotoxicity was observed in CNS-infiltrating lymphocytes following infection of SJL mice with VP1 mutant viruses. The mutant DA-VP1-99(Ser) and DA-VP1(100) viruses were in fact neurovirulent when compared to the wild-type DA virus, as they induced an overwhelming encephalitis and early lethality (2 to 4 days postinfection) in mice deficient in the IFN-alpha/beta receptor. Therefore, the nondemyelinating phenotype observed with DA-VP1-99(Ser) and DA-VP1-100(Asp) viruses is dependent in part on the CD4-mediated host immune response.
Rodriguez
M
M
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA. rodriguez.moses@mayo.edu
Roos
R P
RP
McGavern
D
D
Zoecklein
L
L
Pavelko
K
K
Sang
H
H
Lin
X
X
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002213:Capsid / Q000235:genetics / Q000378:metabolism*; D036022:Capsid Proteins; D018188:Cardiovirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D002460:Cell Line; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology / Q000821:virology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D017403:In Situ Hybridization; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009500:Neutralization Tests; D017354:Point Mutation / Q000235:genetics*; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology; D017945:Theilovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D014774:Virulence
D000914:Antibodies, Viral; D015704:CD4 Antigens; D016827:CD8 Antigens; D036022:Capsid Proteins; D000949:Histocompatibility Antigens Class II; D012367:RNA, Viral; D017471:Receptors, Interferon; C442551:VP1 protein, Theilovirus; D053633:Receptor, Interferon alpha-beta