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Journal of Virology, October 2003, p. 10250-10259, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10250-10259.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku,¹ The Kitasato Institute for Life Sciences, Kitasato University,² Department of Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan,³ LASP/CPqGM/FIOCRUZ-Bahia, Salvador-Bahia CEP 40295-001, Brazil,⁵ Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR CNRS 7627, Hôpital Pitié-Salpêtrière, 75013 Paris, France⁴

Received 7 February 2003/ Accepted 27 June 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.

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