Adenovirus-transduced dendritic cells injected into skin or lymph node prime potent simian immunodeficiency virus-specific T cell immunity in monkeys.
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.
Brown
Kevin
K
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Gao
Wentao
W
Alber
Sean
S
Trichel
Anita
A
Murphey-Corb
Michael
M
Watkins
Simon C
SC
Gambotto
Andrea
A
Barratt-Boyes
Simon M
SM
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015683:Gene Products, gag / Q000096:biosynthesis / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007115:Immunization Schedule; D016056:Immunodominant Epitopes / Q000276:immunology; D007271:Injections, Intradermal; D007272:Injections, Intralymphatic; D008198:Lymph Nodes / Q000276:immunology* / Q000821:virology; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology; D014161:Transduction, Genetic; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D016056:Immunodominant Epitopes; D018449:SAIDS Vaccines; D019444:Vaccines, DNA