title: Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection.
abstract: Persistent viral infections often overburden the immune system and are a major cause of disease in humans. During many persistent infections, antiviral T cells are maintained in a state of immune exhaustion characterized by diminished effector and helper functions. In mammalian systems, an extensive immune regulatory network exists to limit unwanted, potentially fatal immunopathology by inducing T cell exhaustion. However, this regulatory network at times overprotects the host and fosters viral persistence by severely dampening adaptive immune responsiveness. Importantly, recent studies have shown that T cell exhaustion is mediated in part by host immunoregulatory pathways (e.g., programmed death 1 [PD-1], interleukin 10 [IL-10]) and that therapeutic blockade of these pathways either before or during persistent infection can promote viral clearance. Transforming growth factor beta (TGF-β) is another immunosuppressive cytokine known to impede both self- and tumor-specific T cells, but its role in regulating antiviral immunity is not entirely understood. In this study, we inhibited TGF-β with three potent antagonists to determine whether neutralization of this regulatory molecule is a viable approach to control a persistent viral infection. Our results revealed that these inhibitors modestly elevate the number of antiviral T cells following infection with a persistent variant of lymphocytic choriomeningitis virus (LCMV) but have no impact on viral clearance. These data suggest that therapeutic neutralization of TGF-β is not an efficacious means to promote clearance of a persistent viral infection.
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lucile
authors.initials: L
authors.lastname: Garidou
authors.forename: Sara
authors.initials: S
authors.lastname: Heydari
authors.forename: Selamawit
authors.initials: S
authors.lastname: Gossa
authors.forename: Dorian B
authors.initials: DB
authors.lastname: McGavern
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007155:Immunologic Factors / Q000008:administration & dosage*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D016212:Transforming Growth Factor beta