Adenovirus-Transduced Dendritic Cells Injected into Skin or Lymph Node Prime Potent Simian Immunodeficiency Virus-Specific T Cell Immunity in Monkeys

• Published in: The Journal of immunology (1950) 2003-12, Vol.171 (12), p.6875-6882
• Main Authors: Brown, Kevin, Gao, Wentao, Alber, Sean, Trichel, Anita, Murphey-Corb, Michael, Watkins, Simon C, Gambotto, Andrea, Barratt-Boyes, Simon M
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - immunology; Animals; Cell Line; Cell Movement - genetics; Cell Movement - immunology; Cells, Cultured; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - transplantation; Dendritic Cells - virology; Epitopes, T-Lymphocyte - immunology; Gene Products, gag - biosynthesis; Gene Products, gag - genetics; Genetic Vectors; Humans; Immunity, Cellular - genetics; Immunization Schedule; Immunodominant Epitopes - immunology; Injections, Intradermal; Injections, Intralymphatic; Lymph Nodes - immunology; Lymph Nodes - virology; Macaca mulatta; SAIDS Vaccines - administration & dosage; SAIDS Vaccines - genetics; SAIDS Vaccines - immunology; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - pathology; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - immunology; Skin - immunology; Skin - virology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - virology; Transduction, Genetic; Vaccines, DNA - administration & dosage; Vaccines, DNA - genetics; Vaccines, DNA - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.12.6875

Adenoviral vectors can be used to deliver complex Ag to dendritic cells (DC), and thus may be ideal for stimulating broad T cell responses to viral pathogens and tumors. To test this hypothesis in a relevant primate model, we used recombinant adenovirus serotype 5 vectors expressing SIV Gag Ag to transduce monocyte-derived DC from rhesus macaques, and then immunized donor animals either by intradermal or intranodal injections. T cell responses were evaluated by ELISPOT assay using previously frozen PBMC pulsed with pools of 15-mer peptides representing the Gag sequence. Immunization resulted in rapid and potent induction of T cell responses to multiple regions of Gag, with frequencies approaching 1 Gag-specific T cell per 500 uncultured PBMC. Surprisingly, intradermal and intranodal injections generated a similar intensity and breadth of response, indicating that administration of Ag-expressing DC by either route may be equally effective at inducing immune responses. Detailed analysis of two monkeys revealed CD8(+) T cell responses to several peptide epitopes of Gag not previously described, at least two of which are restricted by MHC class I alleles not currently identified. Repeated vaccination did not induce T cell responses to the adenoviral vector and did not prevent Ag-expressing DC injected under the capsule of the lymph node from migrating to the paracortex and interposing between T cells. However, boost injections of adenovirus-transduced DC were generally limited in efficacy. These findings support the use of adenovirus-transduced DC in the therapy of HIV infection and cancer.