ABSTRACT
Human papillomavirus (HPV)-derived chimeric virus-like particles (VLPs) are the leading candidate vaccine for the treatment or prevention of cervical cancer in humans. Dendritic cells (DCs) are the most potent inducers of immune responses and here we show for the first time evidence for binding of chimeric HPV-16 VLPs to human peripheral blood-derived DCS: Incubation of immature human DCs with VLPs for 48 h induced a significant up-regulation of the CD80 and CD83 molecules as well as secretion of IL-12. Confocal microscopy analysis revealed that cell surface-bound chimeric VLPs were taken up by DCS: Moreover, DCs loaded with chimeric HPV-16 L1L2-E7 VLPs induced an HLA-*0201-restricted human T cell response in vitro specific for E7-derived peptides. These results clearly demonstrate that immature human DCs are fully activated by chimeric HPV-16 VLPs and subsequently are capable of inducing endogenously processed epitope-specific human T cell responses in vitro. Overall, these findings could explain the high immunogenicity and efficiency of VLPs as vaccines.
Subject(s)
Capsid Proteins , Dendritic Cells/immunology , Dendritic Cells/virology , Epitopes, T-Lymphocyte/immunology , Papillomaviridae/immunology , Recombinant Fusion Proteins/immunology , T-Lymphocytes, Cytotoxic/immunology , Virion/immunology , Antigen Presentation/genetics , Capsid/genetics , Capsid/immunology , Capsid/metabolism , Cells, Cultured , Dendritic Cells/metabolism , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/metabolism , Humans , Interleukin-12/metabolism , Lipopolysaccharides/immunology , Monocytes/immunology , Monocytes/metabolism , Monocytes/virology , Oncogene Proteins, Viral/genetics , Oncogene Proteins, Viral/immunology , Oncogene Proteins, Viral/metabolism , Papillomaviridae/genetics , Papillomavirus E7 Proteins , Peptide Mapping , Protein Binding/genetics , Protein Binding/immunology , T-Lymphocytes, Cytotoxic/metabolism , Tumor Necrosis Factor-alpha/immunology , Virion/geneticsABSTRACT
Certain human cancers are linked to infection by oncogenic viruses that are able to cause transformation of the normal host cell into a cancerous cell. Human papillomavirus (HPV) DNA and expression of viral transforming proteins are found in virtually all cervical cancer cells, indicating an important role of this virus in the pathogenesis of the disease. Evidence exists that the immune response to cancer cells can play a major role in determining the outcome of disease. The fact that HPV is a necessary cause for cervical cancer provides a clear opportunity to develop a therapeutic vaccine against the virus to treat patients with cervical cancer at its early and late stages. Development of a prophylactic vaccine for HPV would also reduce the incidence of cervical neoplasias by preventing virus infection. Various candidate HPV vaccines are being developed and tested in animal models and/or in human clinical trials. These HPV vaccines, both preventive and therapeutic, are the subjects of this review.
