title: Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection.
abstract: Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8(+) T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8(+) T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4(+) T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Scott N
authors.initials: SN
authors.lastname: Mueller
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Aubert
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D001117:Arenaviridae Infections / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D014765:Viral Vaccines / Q000627:therapeutic use*
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014614:Vaccines, Synthetic; D014765:Viral Vaccines