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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS Vaccines / immunology*
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Amino Acid Sequence
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Base Sequence
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Line
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Chick Embryo
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Cytokines / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Epitopes, T-Lymphocyte / immunology
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Gene Deletion
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Gene Expression
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Gene Order
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Genetic Vectors / genetics
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Genetic Vectors / immunology
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HIV Antigens / genetics
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HIV Antigens / immunology*
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HIV Envelope Protein gp120 / chemistry
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HIV Envelope Protein gp120 / genetics
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HIV Envelope Protein gp120 / immunology
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HIV-1 / genetics
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HIV-1 / immunology*
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Human Immunodeficiency Virus Proteins / chemistry
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Human Immunodeficiency Virus Proteins / genetics
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Human Immunodeficiency Virus Proteins / immunology
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Humans
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Immunologic Memory / immunology
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Interferon Type I / metabolism
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Molecular Sequence Data
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Vaccinia virus / genetics*
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Vaccinia virus / immunology*
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Viral Proteins / genetics*
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Viral Proteins / immunology*
Substances
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AIDS Vaccines
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Cytokines
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Epitopes, T-Lymphocyte
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F1L protein, vaccinia virus
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HIV Antigens
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HIV Envelope Protein gp120
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Human Immunodeficiency Virus Proteins
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Interferon Type I
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Viral Proteins
Grants and funding
This investigation was supported by grants from the Ministry of Science and Innovation of Spain (SAF2008–02036), Foundation FIPSE and PTVDC/CAVD program with support from the Bill and Melinda Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.