title: Increased generation of HIV-1 gp120-reactive CD8+ T cells by a DNA vaccine construct encoding the chemokine CCL3.
abstract: DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV-1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8+ T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.
authors.affiliation: Dept. of Immunology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway; Centre for Immune Regulation, University of Oslo, Oslo, Norway.
authors.forename: Inger
authors.initials: I
authors.lastname: Øynebråten
authors.affiliation: Division of Molecular Virology, Dept. of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Jorma
authors.initials: J
authors.lastname: Hinkula
authors.affiliation: Dept. of Immunology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway; Centre for Immune Regulation, University of Oslo, Oslo, Norway.
authors.forename: Agnete B
authors.initials: AB
authors.lastname: Fredriksen
authors.affiliation: Dept. of Immunology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway; Centre for Immune Regulation, University of Oslo, Oslo, Norway; KG Jebsen Centre for research on Influenza Vaccines, University of Oslo, Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
mesh_terms: D000818:Animals; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D054405:Chemokine CCL3 / Q000235:genetics*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000096:biosynthesis; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D051379:Mice; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
chemical_list: D054405:Chemokine CCL3; D017931:DNA Primers; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D019444:Vaccines, DNA