title: Elimination of chronic viral infection by blocking CD27 signaling.
abstract: Neutralizing antibody (nAb) responses to lymphocytic choriomeningitis virus (LCMV) in mice and immunodeficiency virus and hepatitis C virus in humans are usually weak and slow to develop. This may be the result of structural properties of the surface glycoprotein, a low frequency of B cells with neutralizing specificity, and the necessity of prolonged affinity maturation of specific nAbs. In this study, we show that during LCMV infection, CD27 signaling on CD4+ T cells enhances the secretion of interferon-gamma and tumor necrosis factor-alpha. These inflammatory cytokines lead to the destruction of splenic architecture and immunodeficiency with reduced and delayed virus-specific nAb responses. Consequently, infection with the otherwise persistent LCMV strain Docile was eliminated after CD27 signaling was blocked. Our data provide a novel mechanism by which LCMV avoids nAb responses and suggest that blocking the CD27-CD70 interaction may be an attractive strategy to prevent chronic viral infection.
authors.affiliation: Tumor Immunology, Department of Clinical Research, Institute of Clinical Chemistry, Inselspital, University of Berne, and Department of Pathology, University Hospital, Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Matter
authors.forename: Bernhard
authors.initials: B
authors.lastname: Odermatt
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nuoffer
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D053282:CD27 Ligand; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D006801:Humans; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009500:Neutralization Tests; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; C505772:Cd70 protein, mouse; D008565:Membrane Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma