Strong CD8+ T cell antigenicity and immunogenicity of large foreign proteins incorporated in HIV-1 VLPs able to induce a Nef-dependent activation/maturation of dendritic cells

• Published in: Vaccine Vol. 29; no. 18; pp. 3465 - 3475
• Main Authors: Sistigu, A, Bracci, L, Valentini, M, Proietti, E, Bona, R, Negri, D.R.M, Ciccaglione, A.R, Tritarelli, E, Nisini, R, Equestre, M, Costantino, A, Marcantonio, C, Santini, S.M, Lapenta, C, Donati, S, Tataseo, P, Miceli, M, Cara, A, Federico, M
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 18.04.2011; Elsevier; Elsevier Limited
• Subjects: Acquired immune deficiency syndrome; AIDS; Allergy and Immunology; Animals; Antigen Presentation; antigens; Applied microbiology; Biological and medical sciences; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; Cloning; Cross-presentation; Cross-Priming; CTLs; Dendritic cells; Dendritic Cells - immunology; Experiments; Fundamental and applied biological sciences. Psychology; Genotype & phenotype; HEK293 Cells; Hepatitis; Hepatitis C virus; HIV; HIV-1 - immunology; Human immunodeficiency virus; Human immunodeficiency virus 1; Human papillomavirus; Humans; immune response; Immunity, Cellular; Infectious diseases; Influenza virus; Interferon-gamma - immunology; Kinases; Lymphocytes; Mice; Mice, Inbred C57BL; Microbiology; Miscellaneous; mutants; Nef; nef Gene Products, Human Immunodeficiency Virus - immunology; Orthomyxoviridae; papilloma; pathogens; patients; polypeptides; Proteins; RNA-Binding Proteins - immunology; Signal transduction; Src tyrosine kinases; src-Family Kinases - immunology; tyrosine; vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccines, Virus-Like Particle - immunology; Viral Core Proteins - immunology; Viral infections; Viral Nonstructural Proteins - immunology; Virology; virus-like particles; Viruses; VLPs; Cross-presentation; VLPs; Src tyrosine kinases; Dendritic cells; Nef; CTLs; Dendritic cell; HIV-1 virus; Enzyme; Transferases; Retroviridae; Cytotoxicity; Lentivirus; Protein; Virus; Antigenicity; Immunogenicity; T-Lymphocyte; Human immunodeficiency virus; Protein-tyrosine kinase; CD8 T lymphocyte
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2011.02.059

Abstract Virus-like particles (VLPs) are excellent tools for vaccines against pathogens and tumors. They can accommodate foreign polypeptides whose incorporation efficiency and immunogenicity however decrease strongly with the increase of their size. We recently described the CD8+ T cell immune response against a small foreign antigen (i.e., the 98 amino acid long human papilloma virus E7 protein) incorporated in human immunodeficiency virus (HIV)-1 based VLPs as product of fusion with an HIV-1 Nef mutant (Nefmut ). Here, we extended our previous investigations by testing the antigenic/immunogenic properties of Nefmut -based VLPs incorporating much larger heterologous products, i.e., human hepatitis C virus (HCV) NS3 and influenza virus NP proteins, which are composed of 630 and 498 amino acids, respectively. We observed a remarkable cross-presentation of HCV NS3 in dendritic cells challenged with Nefmut –NS3 VLPs, as detected using a NS3 specific CD8+ T cell clone as well as PBMCs from HCV infected patients. On the other hand, when injected in mice, Nefmut –NP VLPs elicited strong anti-NP CD8+ T cell and CTL immune responses. In addition, we revealed the ability of Nefmut incorporated in VLPs to activate and mature primary human immature dendritic cells (iDCs). This phenomenon correlated with the activation of Src tyrosine kinase-related intracellular signaling, and can be transmitted from VLP-challenged to bystander iDCs. Overall, these results prove that Nefmut -based VLPs represent a rather flexible platform for the design of innovative CD8+ T cell vaccines.