title: Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression.
abstract: The Clone 13 (Cl13) strain of lymphocytic choriomeningitis virus is widely studied as a model of chronic systemic viral infection. Here, we used reverse genetic techniques to identify the molecular basis of Cl13 persistence and immunosuppression, the characteristics differentiating it from the closely related Armstrong strain. We found that a single-point mutation in the Cl13 polymerase was necessary and partially sufficient for viral persistence and immunosuppression. A glycoprotein mutation known to enhance dendritic cell targeting accentuated both characteristics but when introduced alone, failed to alter the phenotype of the Armstrong strain. The decisive polymerase mutation increased intracellular viral RNA load in plasmacytoid dendritic cells, which we identified as a main initial target cell type in vivo, and increased viremia in the early phase of infection. These findings establish the enhanced replicative capacity as the primary determinant of the Cl13 phenotype. Viral persistence and immunosuppression can, thus, represent a direct consequence of excessive viral replication overwhelming the host's antiviral defense.
authors.affiliation: Department of Pathology and Immunology, Centre Médical Universitaire, University of Geneva, 1211 Geneva, Switzerland. andreas.bergthaler@gmail.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.forename: Lukas
authors.initials: L
authors.lastname: Flatz
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.forename: Susan
authors.initials: S
authors.lastname: Johnson
authors.forename: Edit
authors.initials: E
authors.lastname: Horvath
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016679:Genome, Viral; D007165:Immunosuppression Therapy; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014766:Viremia; D014779:Virus Replication
chemical_list: D014764:Viral Proteins