E-GEOD-26239 - Improved Innate and Adaptive Immunostimulation by Genetically Modified HIV-1 Protein Expressing NYVAC Vectors
Released on 21 December 2010, last updated on 26 June 2012
Attenuated poxviruses are safe and capable to express foreign antigens. Poxviruses are applied in veterinary vaccination and explored as candidate vaccines for humans. However, poxviruses express multiple genes encoding proteins that interfere with components of the innate and adaptive immune response. This manuscript describes two strategies aimed to improve the immunogenicity of the highly attenuated, host-range restricted poxvirus NYVAC: deletion of the viral gene encoding type-I interferon-binding protein and development of attenuated replication-competent NYVAC. We evaluated these newly generated NYVAC mutants, encoding HIV-1 env, gag, pol and nef, for their ability to stimulate HIV-specific CD8 T-cell responses from blood mononuclear cells of HIV-infected subjects. The new vectors were evaluated and compared to the parental NYVAC vector in dendritic cells (DCs), RNA expression arrays, HIV gag expression and direct and cross-presentation assays in vitro. Deletion of type-I interferon-binding protein enhanced expression of interferon and interferon-induced genes in DCs, and increased maturation of infected DCs. Restoration of replication competence induced activation of pathways involving antigen processing and presentation. Also, replication-competent NYVAC showed increased Gag expression in infected cells, permitting enhanced cross-presentation to HIV-specific CD8 T cells and proliferation of HIV-specific memory CD8 T-cells. The recombinant NYVAC combining both modifications induced interferon-induced genes and genes involved in antigen processing and presentation, as well as increased Gag expression. This combined replication-competent NYVAC is a promising candidate for the next generation of HIV vaccines. RNA expression obtained from DCs infected by NYVAC-C-dB19R and NYVAC-C-KC-dB19R compared to RNA expression obtained from DCs infected by NYVAC-C Supplementary file 'normalized_data_Human_V3_V2.txt' reports data for ILMN identifiers common to platforms HumanRef8V2 and HumanRef8V3.
transcription profiling by array
Ali Filali <email@example.com>, Abdelali Filali-Mouhim, Alexandre Harari, Anke Redeker, Antonio Lanzavecchia, Beatrice Perdiguero, Bertram Jacobs, Carmen E Gomez, Cornelis J Melief, David M Koelle, Elias K Haddad, Esther D Quakkelaar, Federica Sallusto, Ferry Ossendorp, Giuseppe Pantaleo, Jean-Phillipe Goulet, Jim Tartaglia, Karen Kibler, Mariano Esteban, Nikki M Loof, Paul Heinen, Rafick P Sékaly, Stella M McCaughey, Thomas Duhen
Improved innate and adaptive immunostimulation by genetically modified HIV-1 protein expressing NYVAC vectors. Quakkelaar ED, Redeker A, Haddad EK, Harari A, McCaughey SM, Duhen T, Filali-Mouhim A, Goulet JP, Loof NM, Ossendorp F, Perdiguero B, Heinen P, Gomez CE, Kibler KV, Koelle DM, Sékaly RP, Sallusto F, Lanzavecchia A, Pantaleo G, Esteban M, Tartaglia J, Jacobs BL, Melief CJ. , Europe PMC 21347234