Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus

Dimitrios Moskofidis, M. Battegay, M. Van den Broek, E. Laine, U. Hoffmann-Rohrer, R. M. Zinkernagel

Research output: Contribution to journalArticle

65 Citations (Scopus)

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 (102 p.f.u.) and high doses (107 p.f.u.) of LCMV-Armstrong were cleared rapidly from immunocompetent mice. Inoculation of a high dose (107 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 < 107 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 > 103 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.

Original languageEnglish (US)
Pages (from-to)381-391
Number of pages11
JournalJournal of General Virology
Volume76
Issue number2
StatePublished - Jan 1 1995
Externally publishedYes

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Lymphocytic choriomeningitis virus
Viruses
T-Lymphocytes
T-Lymphocyte Epitopes
Inbred C57BL Mouse
T-Lymphoid Precursor Cells
Phenotype
Viral Antigens
Asparagine
Viral RNA
Infection
Serine
Antiviral Agents
Sequence Analysis
Foot
Glycoproteins

ASJC Scopus subject areas

  • Virology

Cite this

Moskofidis, D., Battegay, M., Van den Broek, M., Laine, E., Hoffmann-Rohrer, U., & Zinkernagel, R. M. (1995). Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus. Journal of General Virology, 76(2), 381-391.

Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus. / Moskofidis, Dimitrios; Battegay, M.; Van den Broek, M.; Laine, E.; Hoffmann-Rohrer, U.; Zinkernagel, R. M.

In: Journal of General Virology, Vol. 76, No. 2, 01.01.1995, p. 381-391.

Research output: Contribution to journalArticle

Moskofidis, D, Battegay, M, Van den Broek, M, Laine, E, Hoffmann-Rohrer, U & Zinkernagel, RM 1995, 'Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus', Journal of General Virology, vol. 76, no. 2, pp. 381-391.
Moskofidis D, Battegay M, Van den Broek M, Laine E, Hoffmann-Rohrer U, Zinkernagel RM. Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus. Journal of General Virology. 1995 Jan 1;76(2):381-391.
Moskofidis, Dimitrios ; Battegay, M. ; Van den Broek, M. ; Laine, E. ; Hoffmann-Rohrer, U. ; Zinkernagel, R. M. / Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus. In: Journal of General Virology. 1995 ; Vol. 76, No. 2. pp. 381-391.
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