PD-1/PD-L1 Blockade Can Enhance HIV-1 Gag-specific T Cell Immunity Elicited by Dendritic Cell-Directed Lentiviral Vaccines

• Published in: Molecular therapy Vol. 20; no. 9; pp. 1800 - 1809
• Main Authors: Dai, Bingbing, Xiao, Liang, Bryson, Paul D, Fang, Jinxu, Wang, Pin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2012; Elsevier Limited; Nature Publishing Group
• Subjects: AIDS Vaccines - administration & dosage; AIDS Vaccines - immunology; Animals; Antibodies; Antigens; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Chemical engineering; Cytokines; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - virology; Enzymes; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Female; gag Gene Products, Human Immunodeficiency Virus; Genetic Vectors; Hepatitis C; HIV; HIV Infections - immunology; HIV Infections - prevention & control; HIV Infections - virology; HIV-1 - genetics; HIV-1 - immunology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immunity, Cellular; Immunization, Secondary; Infections; Lentivirus - genetics; Ligands; Lymphatic system; Lymphocyte Activation; Lymphocytes; Materials science; Mice; Original; Programmed Cell Death 1 Receptor; Spleen; Vaccines; Vaccinia virus; Los Angeles California; United States > US; California
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2012.98

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.