title: Coupling of HIV-1 Antigen to the Selective Autophagy Receptor SQSTM1/p62 Promotes T-Cell-Mediated Immunity.
abstract: Vaccines aiming to promote T-cell-mediated immune responses have so far showed limited efficacy, and there is a need for novel strategies. Studies indicate that autophagy plays an inherent role in antigen processing and presentation for CD4(+) and CD8(+) T cells. Here, we report a novel vaccine strategy based on fusion of antigen to the selective autophagy receptor sequestosome 1 (SQSTM1)/p62. We hypothesized that redirection of vaccine antigen from proteasomal degradation into the autophagy pathway would increase the generation of antigen-specific T cells. A hybrid vaccine construct was designed in which the antigen is fused to the C-terminus of p62, a signaling hub, and a receptor that naturally delivers ubiquitinated cargo for autophagic degradation. Fusion of the human immunodeficiency virus-1 antigen Gagp24 to p62 resulted in efficient antigen delivery into the autophagy pathway. Intradermal immunization of mice revealed that, in comparison to Gagp24 delivered alone, fusion to p62 enhanced the number of Gagp24-specific interferon-γ-producing T cells, including CD8(+) T cells. The strategy may also have the potential to modulate the antigenic peptide repertoire. Because p62 and autophagy are highly conserved between species, we anticipate this strategy to be a candidate for the development of T-cell-based vaccines in humans.
authors.affiliation: Tumor Immunology Group, Department of Pathology, Rikshospitalet, University of Oslo and Oslo University Hospital, Oslo, Norway; Department of Immunology, Rikshospitalet, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Aram Nikolai
authors.initials: AN
authors.lastname: Andersen
authors.affiliation: Centre for Immune Regulation, University of Oslo, Oslo, Norway; LIIPAT, Department of Pathology, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
authors.forename: Ole Jørgen
authors.initials: OJ
authors.lastname: Landsverk
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo , Oslo , Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
authors.affiliation: Department of Immunology, Rikshospitalet, University of Oslo and Oslo University Hospital, Oslo, Norway; Centre for Immune Regulation, University of Oslo, Oslo, Norway; K. G. Jebsen Centre for Influenza Research, University of Oslo, Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
authors.affiliation: Tumor Immunology Group, Department of Pathology, Rikshospitalet, University of Oslo and Oslo University Hospital , Oslo , Norway.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Corthay
authors.affiliation: Tumor Immunology Group, Department of Pathology, Rikshospitalet, University of Oslo and Oslo University Hospital, Oslo, Norway; Department of Immunology, Rikshospitalet, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Inger
authors.initials: I
authors.lastname: Øynebråten
keywords: HIV-1 gagp24 antigen; T cell responses; autophagy; p62/SQSTM1; vaccine