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


Moskophidis, 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.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:February 1995
Deposited On:08 Feb 2018 15:00
Last Modified:20 Feb 2018 11:57
Publisher:Society for General Microbiology
ISSN:0022-1317
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1099/0022-1317-76-2-381
PubMed ID:7531218

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