Yeast-derived human immunodeficiency virus type 1 p55(gag) virus-like particles activate dendritic cells (DCs) and induce perforin expression in Gag-specific CD8(+) T cells by cross-presentation of DCs

• Published in: Journal of virology 2003-10, Vol.77 (19), p.10250-10259
• Main Authors: Tsunetsugu-Yokota, Yasuko, Morikawa, Yuko, Isogai, Maya, Kawana-Tachikawa, Ai, Odawara, Takashi, Nakamura, Tetsuya, Grassi, Fernanda, Autran, Brigitte, Iwamoto, Aikichi
• Format: Article
• Language: English
• Subjects: Antigen Presentation; CD8-Positive T-Lymphocytes - immunology; Coculture Techniques; Dendritic Cells - physiology; Gene Products, gag - physiology; HIV-1 - physiology; Humans; Interferon-gamma - biosynthesis; Interleukin-12 - biosynthesis; Lymphocyte Activation; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - physiology; Perforin; Pore Forming Cytotoxic Proteins; Protein Precursors - physiology; Receptors, Cell Surface - physiology; Saccharomyces cerevisiae - genetics; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptors; Virion - physiology
• ISSN: 0022-538X
• DOI: 10.1128/JVI.77.19.10250-10259.2003

To evaluate the immunogenicity of human immunodeficiency virus (HIV) type 1 p55(gag) virus-like particles (VLPs) released by budding from yeast spheroplasts, we have analyzed the effects of yeast VLPs on monocyte-derived dendritic cells (DCs). Yeast VLPs were efficiently incorporated into DCs via both macropinocytosis and endocytosis mediated by mannose-recognizing receptors, but not the mannose receptor. The uptake of yeast VLPs induced DC maturation and enhanced cytokine production, notably, interleukin-12 p70. We showed that yeast membrane components may contribute to DC maturation partly through Toll-like receptor 2 signaling. Thus, Gag particles encapsulated by yeast membrane may have an advantage in stimulating Gag-specific immune responses. We found that yeast VLPs, but not the control yeast membrane fraction, were able to activate both CD4(+) and CD8(+) T cells of HIV-infected individuals. We tested the effect of cross-presentation of VLP by DCs in two subjects recruited into a long-term nonprogressor-slow progressor cohort. When yeast VLP-loaded DCs of these patients were cocultured with peripheral blood mononuclear cells for 7 days, approximately one-third of the Gag-specific CD8(+) T cells were activated and became perforin positive. However, some of the Gag-specific CD8(+) T cells appeared to be lost during in vitro culture, especially in a patient with a high virus load. Our results suggest that DCs loaded with yeast VLPs can activate Gag-specific memory CD8(+) T cells to become effector cells in chronically HIV-infected individuals, but there still remain unresponsive Gag-specific T-cell populations in these patients.