title: Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus.
abstract: C57BL/6 mice infected with increasing doses of the Armstrong isolate of lymphocytic choriomeningitis virus (LCMV) or a variant Cl 13-Armstrong, derived from LCMV-Armstrong, exhibited distinct phenotypes with respect to clearance of virus and to cytotoxic CD8+ T cell (CTL)-dependent immunopathological disease. Low (10(2) p.f.u.) and high doses (10(7) p.f.u.) of LCMV-Armstrong were cleared rapidly from immunocompetent mice. Inoculation of a high dose (10(7) p.f.u.) of LCMV Cl 13-Armstrong temporarily induced a partial deletion of the antiviral CTL precursors (CTL-p) leading to chronic infection in several organs. Although virus was cleared from most organs by day 90-150 post-infection, it persisted in the kidney. The few remaining CTL-p were able to expand and eventually clear the virus. Systemic viral titres correlated inversely with the number of CTL-p. However, in contrast LCMV-Docile injected at high dose was able to cause complete exhaustion of CTL-p resulting in long term viral persistence. LCMV-Aggressive, derived from the same parental LCMV-WE (UBC) as Docile, showed a phenotype comparable to wild-type virus. Doses of < 10(7) p.f.u. of both Armstrong virus and of Cl 13-Armstrong failed to exhaust CTL-p and caused lethal CD8+ T cell-dependent choriomeningitis and a substantial footpad swelling after local infection. By contrast, doses > 10(3) p.f.u. of LCMV-Docile failed to cause lethal choriomeningitis in C57BL/6 mice. When Cl 13-Armstrong virus (but not LCMV-Armstrong) was injected intravenously in addition to intracerebrally or into the foot, the local immunopathology was abrogated in a dose-dependent fashion. The suppression of immunopathology paralleled the extent of exhaustion of the specific CD8+ T cell response. Nucleotide sequence analysis of the viral S-RNA fragments coding for CTL epitopes in H-2b mice revealed an asparagine to serine change of amino acid 280 in the CTL epitope 275-286 of the LCMV-Docile glycoprotein (GP) in comparison to LCMV-Aggressive or wild-type WE. This change reduced overall CTL activity and thereby probably contributes to exhaustion of CTL responses in C57BL/6 (H-2b) mice. Thus, local versus systemic antigen distribution, viral characteristics and immunological parameters determine induction and exhaustion of CD8+ T cells and the course and extent of immunopathological disease.
authors.affiliation: Department of Pathology, University of Zürich, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Moskophidis
authors.forename: M
authors.initials: M
authors.lastname: Battegay
authors.forename: M
authors.initials: M
authors.lastname: van den Broek
authors.forename: E
authors.initials: E
authors.lastname: Laine
authors.forename: U
authors.initials: U
authors.lastname: Hoffmann-Rohrer
authors.forename: R M
authors.initials: RM
authors.lastname: Zinkernagel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001483:Base Sequence; D000939:Epitopes; D006183:H-2 Antigens / Q000235:genetics; D006239:Haplotypes; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D000939:Epitopes; D006183:H-2 Antigens