title: Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection.
abstract: Failure to clear persistent viral infections results from the early loss of T cell activity. A pertinent question is whether the immune response is programmed to fail or if nonresponsive T cells can specifically be fixed to eliminate infection. Although evidence indicates that T cell expansion is permanently programmed during the initial priming events, the mechanisms that determine the acquisition of T cell function are less clear. Herein we show that in contrast to expansion, the functional programming of T cell effector and memory responses in vivo in mice is not hardwired during priming but is alterable and responsive to continuous instruction from the antigenic environment. As a direct consequence, dysfunctional T cells can be functionally reactivated during persistent infection even after an initial program of inactivation has been instituted. We also show that early therapeutic reductions in viral replication facilitate the preservation of antiviral CD4+ T cell activity, enabling the long-term control of viral replication. Thus, dysfunctional antiviral T cells can regain activity, providing a basis for future therapeutic strategies to treat persistent viral infections.
authors.affiliation: Viral Immunobiology Laboratory, Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, California, USA. dbrooks@scripps.edu
authors.forename: David G
authors.initials: DG
authors.lastname: Brooks
authors.forename: Dorian B
authors.initials: DB
authors.lastname: McGavern
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012254:Ribavirin / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D015704:CD4 Antigens; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D012254:Ribavirin; D007371:Interferon-gamma