Abstract
Current human immunodeficiency virus (HIV) vaccine approaches emphasize prime boost strategies comprising multiple doses of DNA vaccine and recombinant viral vectors. We are developing a protein-based approach that directly harnesses principles for generating T cell immunity. Vaccine is delivered to maturing dendritic cells in lymphoid tissue by engineering protein antigen into an antibody to DEC-205, a receptor for antigen presentation. Here we characterize the CD4+ T cell immune response to HIV gag and compare efficacy with other vaccine strategies in a single dose. DEC-205-targeted HIV gag p24 or p41 induces stronger CD4+ T cell immunity relative to high doses of gag protein, HIV gag plasmid DNA, or recombinant adenovirus-gag. High frequencies of interferon (IFN)-gamma- and interleukin 2-producing CD4+ T cells are elicited, including double cytokine-producing cells. In addition, the response is broad because the primed mice respond to an array of peptides in different major histocompatibility complex haplotypes. Long-lived T cell memory is observed. After subcutaneous vaccination, CD4+ and IFN-gamma-dependent protection develops to a challenge with recombinant vaccinia-gag virus at a mucosal surface, the airway. We suggest that a DEC-targeted vaccine, in part because of an unusually strong and protective CD4+ T cell response, will improve vaccine efficacy as a stand-alone approach or with other modalities.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AIDS Vaccines / administration & dosage
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AIDS Vaccines / genetics
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AIDS Vaccines / immunology*
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Adenoviridae
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / genetics
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Antibodies, Monoclonal / immunology
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Antigen Presentation / drug effects
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Antigen Presentation / immunology
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Antigens, CD / genetics
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Antigens, CD / immunology*
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CD4-Positive T-Lymphocytes / immunology*
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Dendritic Cells / immunology*
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Dose-Response Relationship, Immunologic
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Gene Products, gag / administration & dosage
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Gene Products, gag / genetics
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Gene Products, gag / immunology*
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Genetic Vectors / administration & dosage
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Genetic Vectors / genetics
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Genetic Vectors / immunology
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HIV-1 / genetics
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HIV-1 / immunology*
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Haplotypes / genetics
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Haplotypes / immunology
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Humans
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Immunity, Mucosal / drug effects
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Immunity, Mucosal / immunology
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Immunologic Memory / drug effects
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Immunologic Memory / immunology
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Injections, Subcutaneous
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Lectins, C-Type / deficiency
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology*
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Major Histocompatibility Complex / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Knockout
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Minor Histocompatibility Antigens
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Vaccinia virus
Substances
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AIDS Vaccines
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Antibodies, Monoclonal
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Antigens, CD
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DEC-205 receptor
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Gene Products, gag
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Lectins, C-Type
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Minor Histocompatibility Antigens
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Receptors, Cell Surface
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Recombinant Fusion Proteins