Effects of an epitope-specific CD8+ T-cell response on murine coronavirus central nervous system disease: protection from virus replication and antigen spread and selection of epitope escape mutants.
Both CD4(+) and CD8(+) T cells are required for clearance of the murine coronavirus mouse hepatitis virus (MHV) during acute infection. We investigated the effects of an epitope-specific CD8(+) T-cell response on acute infection of MHV, strain A59, in the murine CNS. Mice with CD8(+) T cells specific for gp33-41 (an H-2D(b)-restricted CD8(+) T-cell epitope derived from lymphocytic choriomeningitis glycoprotein) were infected with a recombinant MHV-A59, also expressing gp33-41, as a fusion protein with enhanced green fluorescent protein (EGFP). By 5 days postinfection, these mice showed significantly (approximately 20-fold) lower titers of infectious virus in the brain compared to control mice. Furthermore mice with gp33-41-specific CD8(+) cells exhibited much reduced levels of viral antigen in the brain as measured by immunohistochemistry using an antibody directed against viral nucleocapsid. More than 90% of the viruses recovered from brain lysates of such protected mice, at 5 days postinfection, had lost the ability to express EGFP and had deletions in their genomes encompassing EGFP and gp33-41. In addition, genomes of viruses from about half the plaques that retained the EGFP gene had mutations within the gp33-41 epitope. On the other hand, gp33-41-specific cells failed to protect perforin-deficient mice from infection by the recombinant MHV expressing gp33, indicating that perforin-mediated mechanisms were needed. Virus recovered from perforin-deficient mice did not exhibit loss of EGFP expression and the gp33-41 epitope. These observations suggest that the cytotoxic T-cell response to gp33-41 exerts a strong immune pressure that quickly selects epitope escape mutants to gp33-41.
Chua
Ming Ming
MM
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076, USA.
MacNamara
Katherine C
KC
San Mateo
Lani
L
Shen
Hao
H
Weiss
Susan R
SR
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D020805:Central Nervous System Viral Diseases / Q000276:immunology* / Q000517:prevention & control; D018352:Coronavirus Infections / Q000276:immunology / Q000517:prevention & control; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology*; D049452:Green Fluorescent Proteins; D006801:Humans; D007114:Immunization; D008164:Luminescent Proteins / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology*; D014779:Virus Replication
D000956:Antigens, Viral; D000939:Epitopes; D006023:Glycoproteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D054353:Perforin; D049452:Green Fluorescent Proteins