title: PD-1/PD-L1 blockade can enhance HIV-1 Gag-specific T cell immunity elicited by dendritic cell-directed lentiviral vaccines.
abstract: Exhaustion of CD8(+) T cells and upregulation of programmed death 1 (PD-1), a negative regulator of T cell activation, are characteristic features of individuals chronically infected with human immunodeficiency virus type 1. In a previous study, we showed in mice that a dendritic cell-directed lentiviral vector (DCLV) system encoding the human immunodeficiency virus (HIV)-1 Gag protein was an efficient vaccine modality to induce a durable Gag-specific T cell immune response. In this study, we demonstrate that blocking of the PD-1/PD-1 ligand (PD-L) inhibitory signal via an anti-PD-L1 antibody generated an enhanced HIV-1 Gag-specific CD8(+) immune response following both a single round of DCLV immunization and a homologous prime/boost regimen. The prime/boost regimen combined with PD-L1 blockade generated very high levels of Gag-specific CD8(+) T cells comprising several valuable features: improved ability to produce multiple cytokines, responding to a broader range of Gag-derived epitopes, and long-lasting memory. This enhanced cellular immune response generated by DCLV immunization combined with anti-PD-L1 blockade correlated with improved viral control following challenge with Gag-expressing vaccinia virus. Taken together, our studies offer evidence to support the use of PD-1/PD-L1 blockade as an adjuvant modality to enhance antigen-specific immune responses elicited by T cell-based immunizations such as DCLV.
authors.affiliation: Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Dai
authors.affiliation: Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bryson
authors.affiliation: Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA.
authors.forename: Jinxu
authors.initials: J
authors.lastname: Fang
authors.affiliation: Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA. Electronic address: pinwang@usc.edu.
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007117:Immunization, Secondary; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D061026:Programmed Cell Death 1 Receptor; D014616:Vaccinia virus; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D016915:AIDS Vaccines; D000943:Antigens, Differentiation; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D018984:Epitopes, T-Lymphocyte; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054301:gag Gene Products, Human Immunodeficiency Virus