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

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

doi:10.1371/journal.pone.0016819

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Journal article

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

Quakkelaar, Esther D. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Redeker, Anke Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Haddad, Elias K. Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), Montreal, Canada
Harari, Alexandre Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland - Swiss Vaccine Research Institute, Lausanne, Switzerland
McCaughey, Stella Mayo Department of Medicine, University of Washington, Seattle, Washington, United States of America
Duhen, Thomas Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Filali-Mouhim, Abdelali Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), Montreal, Canada
Goulet, Jean-Philippe Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), Montreal, Canada
Loof, Nikki M. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Ossendorp, Ferry Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Perdiguero, Beatriz Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Heinen, Paul Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Gomez, Carmen E. Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Kibler, Karen V. Arizona State University, Tempe, Arizona, United States of America
Koelle, David M. Department of Medicine, University of Washington, Seattle, Washington, United States of America - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
Sékaly, Rafick P. Laboratoire d’Immunologie, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), Montreal, Canada
Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Pantaleo, Giuseppe Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland - Swiss Vaccine Research Institute, Lausanne, Switzerland
Esteban, Mariano Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Tartaglia, Jim Sanofi Pasteur, Swiftwater, Pennsylvania, United States of America
Jacobs, Bertram L. Arizona State University, Tempe, Arizona, United States of America
Melief, Cornelis J. M. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands - ISA Pharmaceuticals B.V., Bilthoven, The Netherlands

15.02.2011

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Plos one. - 2011, vol. 6, no. 2, p. e16819

English 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 crosspresentation assays in vitro. Deletion of type-I interferon-binding protein enhanced expression of interferon and interferoninduced genes in DCs, and increased maturation of infected DCs. Restoration of replication competence induced activationof 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 HIVspecific 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.

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