Yeast-Derived Human Immunodeficiency Virus Type 1 p55^gagVirus-Like Particles Activate Dendritic Cells (DCs) and Induce Perforin Expression in Gag-Specific CD8⁺T Cells by Cross-Presentation of DCs

Abstract

To evaluate the immunogenicity of human immunodeficiency virus (HIV) type 1 p55gag virus-like particles (VLPs) released by budding from yeast spheroplasts, we have analyzed the effects of yeast VLPs on monocytederived 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.

Novel Plant Virus-Based Vaccine Induces Protective Cytotoxic T-Lymphocyte-Mediated Antiviral Immunity through Dendritic Cell Maturation

“…These results suggest that PapMV VLPs possess an intrinsic adjuvant-like property that induces DC maturation. Compared to other VLP-based systems, PapMV VLPs seem to be one of the more potent at inducing the upregulation of cosignaling molecules on DCs (15,18,40,41).…”

Baculovirus-Derived Human Immunodeficiency Virus Type 1 Virus-Like Particles Activate Dendritic Cells and Induce Ex Vivo T-Cell Responses

“…The apparent discordance of these results could be due to a different optimal timing for the sample collection and needs to be evaluated by more extensive observations. Nevertheless, the production of IFN-␥ by DCs induced with enveloped or nonenveloped VLP produced in different expression systems (prokaryotic, yeast, and baculovirus) is still a debated issue (18,28,30,49,53,54). In particular, Yang et al (53), reported that the CD8␣ ϩ…”

“…Additional studies will be necessary to evaluate the role of other TLRs in the baculovirus-expressed HIV-VLP-induced activation of MDDCs. Yeast-derived HIV-VLPs have been previously shown to activate MDDCs through the TLR2 (49), suggesting that the expression system used for the VLP production may significantly influence the pathway involved in the biological effects induced on APCs.…”

“…Nonenveloped human papillomavirus-based VLPs have been reported to induce activation and maturation of DCs through the TLR4 (28,29,52). Similarly, yeast-derived HIV-VLPs have been shown to activate DCs partially through the TLR2 signaling pathway (49). Our enveloped HIV-VLPs are produced in a baculovirus expression system, presenting a whole gp120 molecule on the surface within a cell membrane environment which may influence the mechanisms of interaction between VLPs and APCs and the pattern of secreted Th-polarizing cytokines.…”

Mutation-Selective Tumor Remission with Ras-Targeted, Whole Yeast-Based Immunotherapy

“…Because yeast exhibits molecular patterns typically associated with pathogens, dendritic cells mature and become activated after receptor-mediated yeast phagocytosis (4). The heterologous tumor antigens expressed in yeast are digested into peptides for presentation via class II and class I MHC receptors that trigger the activation of antigen-specific cytotoxic T lymphocytes (CTL) and helper T cells (4,6,7,11). Prophylactic immunization of mice with ovalbumin-expressing yeast elicited immune-mediated rejection of transplanted ovalbumin-transfected lymphomas or melanomas (Ref.…”