A synthetic codon-optimized hepatitis C virus nonstructural 5A DNA vaccine primes polyfunctional CD8+ T cell responses in wild-type and NS5A-transgenic mice
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A synthetic codon-optimized hepatitis C virus nonstructural 5A DNA vaccine primes polyfunctional CD8+ T cell responses in wild-type and NS5A-transgenic mice. / Holmström, Fredrik; Pasetto, Anna; Nähr, Veronica; Brass, Anette; Kriegs, Malte; Hildt, Eberhard; Broderick, Kate E; Chen, Margaret; Ahlén, Gustaf; Frelin, Lars.
in: J IMMUNOL, Jahrgang 190, Nr. 3, 01.02.2013, S. 1113-24.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A synthetic codon-optimized hepatitis C virus nonstructural 5A DNA vaccine primes polyfunctional CD8+ T cell responses in wild-type and NS5A-transgenic mice
AU - Holmström, Fredrik
AU - Pasetto, Anna
AU - Nähr, Veronica
AU - Brass, Anette
AU - Kriegs, Malte
AU - Hildt, Eberhard
AU - Broderick, Kate E
AU - Chen, Margaret
AU - Ahlén, Gustaf
AU - Frelin, Lars
PY - 2013/2/1
Y1 - 2013/2/1
N2 - The hepatitis C virus (HCV) nonstructural (NS) 5A protein has been shown to promote viral persistence by interfering with both innate and adaptive immunity. At the same time, the HCV NS5A protein has been suggested as a target for antiviral therapy. In this study, we performed a detailed characterization of HCV NS5A immunogenicity in wild-type (wt) and immune tolerant HCV NS5A-transgenic (Tg) C57BL/6J mice. We evaluated how efficiently HCV NS5A-based genetic vaccines could activate strong T cell responses. Truncated and full-length wt and synthetic codon-optimized NS5A genotype 1b genes were cloned into eukaryotic expression plasmids, and the immunogenicity was determined after i.m. immunization in combination with in vivo electroporation. The NS5A-based genetic vaccines primed high Ab levels, with IgG titers of >10(4) postimmunization. With respect to CD8(+) T cell responses, the coNS5A gene primed more potent IFN-γ-producing and lytic cytotoxic T cells in wt mice compared with NS5A-Tg mice. In addition, high frequencies of NS5A-specific CD8(+) T cells were found in wt mice after a single immunization. To test the functionality of the CTL responses, the ability to inhibit growth of NS5A-expressing tumor cells in vivo was analyzed after immunization. A single dose of coNS5A primed tumor-inhibiting responses in both wt and NS5A-Tg mice. Finally, immunization with the coNS5A gene primed polyfunctional NS5A-specific CD8(+) T cell responses. Thus, the coNS5A gene is a promising therapeutic vaccine candidate for chronic HCV infections.
AB - The hepatitis C virus (HCV) nonstructural (NS) 5A protein has been shown to promote viral persistence by interfering with both innate and adaptive immunity. At the same time, the HCV NS5A protein has been suggested as a target for antiviral therapy. In this study, we performed a detailed characterization of HCV NS5A immunogenicity in wild-type (wt) and immune tolerant HCV NS5A-transgenic (Tg) C57BL/6J mice. We evaluated how efficiently HCV NS5A-based genetic vaccines could activate strong T cell responses. Truncated and full-length wt and synthetic codon-optimized NS5A genotype 1b genes were cloned into eukaryotic expression plasmids, and the immunogenicity was determined after i.m. immunization in combination with in vivo electroporation. The NS5A-based genetic vaccines primed high Ab levels, with IgG titers of >10(4) postimmunization. With respect to CD8(+) T cell responses, the coNS5A gene primed more potent IFN-γ-producing and lytic cytotoxic T cells in wt mice compared with NS5A-Tg mice. In addition, high frequencies of NS5A-specific CD8(+) T cells were found in wt mice after a single immunization. To test the functionality of the CTL responses, the ability to inhibit growth of NS5A-expressing tumor cells in vivo was analyzed after immunization. A single dose of coNS5A primed tumor-inhibiting responses in both wt and NS5A-Tg mice. Finally, immunization with the coNS5A gene primed polyfunctional NS5A-specific CD8(+) T cell responses. Thus, the coNS5A gene is a promising therapeutic vaccine candidate for chronic HCV infections.
KW - Animals
KW - Antibody Specificity
KW - Antigens, Neoplasm
KW - CD8-Positive T-Lymphocytes
KW - Cancer Vaccines
KW - Codon
KW - Cytotoxicity, Immunologic
KW - DNA, Viral
KW - Genes, Synthetic
KW - H-2 Antigens
KW - Hepacivirus
KW - Hepatitis C Antibodies
KW - Immunization
KW - Immunoglobulin G
KW - Lymphocyte Activation
KW - Lymphokines
KW - Lymphoma, Non-Hodgkin
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Peptide Fragments
KW - T-Cell Antigen Receptor Specificity
KW - T-Lymphocytes, Cytotoxic
KW - Vaccines, DNA
KW - Viral Hepatitis Vaccines
KW - Viral Nonstructural Proteins
U2 - 10.4049/jimmunol.1201497
DO - 10.4049/jimmunol.1201497
M3 - SCORING: Journal article
C2 - 23284053
VL - 190
SP - 1113
EP - 1124
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 3
ER -