Improved innate and adaptive immunostimulation by genetically modified HIV-1 protein expressing NYVAC vectors

Esther D. Quakkelaar, Anke Redeker, Elias K. Haddad, Alexandre Harari, Stella Mayo McCaughey, Thomas Duhen, Abdelali Filali-Mouhim, Jean Philippe Goulet, Nikki M. Loof, Ferry Ossendorp, Beatriz Perdiguero, Paul Heinen, Carmen E. Gomez, Karen Kibler, David M. Koelle, Rafick P. Sékaly, Federica Sallusto, Antonio Lanzavecchia, Giuseppe Pantaleo, Mariano EstebanJim Tartaglia, Bertram Jacobs, Cornelis J M Melief

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Attenuated poxviruses are safe and capable of expressing 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 in vitro 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 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 in vitro. 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.

Original languageEnglish (US)
Article numbere16819
JournalPloS one
Volume6
Issue number2
DOIs
StatePublished - Feb 28 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Quakkelaar, E. D., Redeker, A., Haddad, E. K., Harari, A., McCaughey, S. M., Duhen, T., Filali-Mouhim, A., Goulet, J. P., Loof, N. M., Ossendorp, F., Perdiguero, B., Heinen, P., Gomez, C. E., Kibler, K., Koelle, D. M., Sékaly, R. P., Sallusto, F., Lanzavecchia, A., Pantaleo, G., ... Melief, C. J. M. (2011). Improved innate and adaptive immunostimulation by genetically modified HIV-1 protein expressing NYVAC vectors. PloS one, 6(2), [e16819]. https://doi.org/10.1371/journal.pone.0016819