Abstract
Potent and broad cellular immune responses against the nonstructural (NS) proteins of hepatitis C virus (HCV) are associated with spontaneous viral clearance. In this study, we have improved the immunogenicity of an adenovirus (Ad)-based HCV vaccine by fusing NS3 from HCV (Strain J4; Genotype 1b) to the MHC class II chaperone protein invariant chain (Ii). We found that, after a single vaccination of C57BL/6 or BALB/c mice with Ad-IiNS3, the HCV NS3-specific CD8(+) T cell responses were significantly enhanced, accelerated, and prolonged compared with the vaccine encoding NS3 alone. The AdIiNS3 vaccination induced polyfunctional CD8(+) T cells characterized by coproduction of IFN-γ, TNF-α and IL-2, and this cell phenotype is associated with good viral control. The memory CD8(+) T cells also expressed high levels of CD27 and CD127, which are markers of long-term survival and maintenance of T cell memory. Functionally, the AdIiNS3-vaccinated mice had a significantly increased cytotoxic capacity compared with the AdNS3 group. The AdIiNS3-induced CD8(+) T cells protected mice from infection with recombinant vaccinia virus expressing HCV NS3 of heterologous 1b strains, and studies in knockout mice demonstrated that this protection was mediated primarily through IFN-γ production. On the basis of these promising results, we suggest that this vaccination technology should be evaluated further in the chimpanzee HCV challenge model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Adenoviridae / immunology*
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Animals
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Antigens, Differentiation, B-Lymphocyte / administration & dosage
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / immunology*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Cell Survival / genetics
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Cell Survival / immunology
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Cytotoxicity Tests, Immunologic / methods
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Disease Models, Animal
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Female
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Genetic Vectors / administration & dosage
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Genetic Vectors / immunology*
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Hepacivirus / genetics
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Hepacivirus / immunology*
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Hepatitis C / immunology
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Hepatitis C / pathology
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Hepatitis C / prevention & control
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Histocompatibility Antigens Class II / administration & dosage
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Histocompatibility Antigens Class II / chemistry
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology*
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Immunologic Memory / genetics
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Immunophenotyping
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Interleukin-7 Receptor alpha Subunit / biosynthesis
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Interleukin-7 Receptor alpha Subunit / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
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Vaccinia virus / genetics
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Vaccinia virus / immunology
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Viral Hepatitis Vaccines / administration & dosage
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Viral Hepatitis Vaccines / genetics
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Viral Hepatitis Vaccines / immunology*
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Viral Nonstructural Proteins / administration & dosage
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / immunology*
Substances
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Antigens, Differentiation, B-Lymphocyte
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Epitopes, T-Lymphocyte
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Histocompatibility Antigens Class II
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Interleukin-7 Receptor alpha Subunit
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NS3 protein, hepatitis C virus
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Recombinant Fusion Proteins
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Viral Hepatitis Vaccines
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Viral Nonstructural Proteins
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invariant chain