The role of CC chemokine receptor 5 in antiviral immunity.
The CC chemokine receptor CCR5 is an important coreceptor for human immunodeficiency virus (HIV), and there is a major thrust to develop anti-CCR5-based therapies for HIV-1. However, it is not known whether CCR5 is critical for a normal antiviral T-cell response. This study investigated the immune response to lymphocytic choriomeningitis virus in mice lacking CCR5 (CCR5(-/-) mice). This infection is a classical model for studying antiviral immunity, and influx of CCR5-expressing CD8(+) T cells and macrophages is essential for both virus control and associated immunopathology. Results showed that the virus-induced clonal expansion of antigen-specific T cells was augmented in CCR5(-/-) mice especially with regard to the CD4(+) subset. Despite absence of CCR5, intracerebral infection invariably resulted in lethal T cell-mediated meningitis, and quantitative and qualitative analysis of the inflammatory exudate cells did not reveal any significant differences between gene-targeted mice and wild-type controls. CCR5 was also found to be redundant regarding the ability to eliminate virus from internal organs. Using delayed-type hypersensitivity to evaluate CD8(+) T cell-mediated inflammation, no significant influence of CCR5 was found, not even when viral peptide was used as local trigger instead of live virus. Finally, long-term CD8(+) T cell-mediated immune surveillance was efficiently sustained in CCR5(-/-) mice. Taken together, these results indicate that expression of CCR5 is not critical for T cell-mediated antiviral immunity, and this molecule may therefore constitute a logic and safe target for anti-HIV therapies.
Nansen
Anneline
A
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
Christensen
Jan Pravsgaard
JP
Andreasen
Susanne Ørding
SØ
Bartholdy
Christina
C
Christensen
Jeanette Erbo
JE
Thomsen
Allan Randrup
AR
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D007109:Immunity; D008213:Lymphocyte Activation / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008587:Meningitis, Viral / Q000209:etiology / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*
D000956:Antigens, Viral; D019713:Receptors, CCR5