title: Deletion of the viral anti-apoptotic gene F1L in the HIV/AIDS vaccine candidate MVA-C enhances immune responses against HIV-1 antigens.
abstract: Vaccinia virus (VACV) encodes an anti-apoptotic Bcl-2-like protein F1 that acts as an inhibitor of caspase-9 and of the Bak/Bax checkpoint but the role of this gene in immune responses is not known. Because dendritic cells that have phagocytosed apoptotic infected cells cross-present viral antigens to cytotoxic T cells inducing an antigen-specific immunity, we hypothesized that deletion of the viral anti-apoptotic F1L gene might have a profound effect on the capacity of poxvirus vectors to activate specific immune responses to virus-expressed recombinant antigens. This has been tested in a mouse model with an F1L deletion mutant of the HIV/AIDS vaccine candidate MVA-C that expresses Env and Gag-Pol-Nef antigens (MVA-C-ΔF1L). The viral gene F1L is not required for virus replication in cultured cells and its deletion in MVA-C induces extensive apoptosis and expression of immunomodulatory genes in infected cells. Analysis of the immune responses induced in BALB/c mice after DNA prime/MVA boost revealed that, in comparison with parental MVA-C, the mutant MVA-C-ΔF1L improves the magnitude of the HIV-1-specific CD8 T cell adaptive immune responses and impacts on the CD8 T cell memory phase by enhancing the magnitude of the response, reducing the contraction phase and changing the memory differentiation pattern. These findings reveal the immunomodulatory role of F1L and that the loss of this gene is a valid strategy for the optimization of MVA as vaccine vector.
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Perdiguero
authors.forename: Carmen Elena
authors.initials: CE
authors.lastname: Gómez
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Nájera
authors.forename: Carlos Oscar S
authors.initials: CO
authors.lastname: Sorzano
authors.forename: Julie
authors.initials: J
authors.lastname: Delaloye
authors.forename: Rubén
authors.initials: R
authors.lastname: González-Sanz
authors.forename: Victoria
authors.initials: V
authors.lastname: Jiménez
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002642:Chick Embryo; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D017353:Gene Deletion; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007370:Interferon Type I / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; C507356:F1L protein, vaccinia virus; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D054298:Human Immunodeficiency Virus Proteins; D007370:Interferon Type I; D014764:Viral Proteins