title: DNA vaccine expressing the non-structural proteins of hepatitis C virus diminishes the expression of HCV proteins in a mouse model.
abstract: Most of the people infected with hepatitis C virus (HCV) develop chronic hepatitis, which in some cases progresses to cirrhosis and ultimately to hepatocellular carcinoma. Although various immunotherapies against the progressive disease status of HCV infection have been studied, a preventive or therapeutic vaccine against this pathogen is still not available. In this study, we constructed a DNA vaccine expressing an HCV structural protein (CN2), non-structural protein (N25) or the empty plasmid DNA as a control and evaluated their efficacy as a candidate HCV vaccine in C57BL/6 and novel genetically modified HCV infection model (HCV-Tg) mice. Strong cellular immune responses to several HCV structural and non-structural proteins, characterized by cytotoxicity and interferon-gamma (IFN-γ) production, were observed in CN2 or N25 DNA vaccine-immunized C57BL/6 mice but not in empty plasmid DNA-administered mice. The therapeutic effects of these DNA vaccines were also examined in HCV-Tg mice that conditionally express HCV proteins in their liver. Though a reduction in cellular immune responses was observed in HCV-Tg mice, there was a significant decrease in the expression of HCV protein in mice administered the N25 DNA vaccine but not in mice administered the empty plasmid DNA. Moreover, both CD8(+) and CD4(+) T cells were required for the decrease of HCV protein in the liver. We found that the N25 DNA vaccine improved pathological changes in the liver compared to the empty plasmid DNA. Thus, these DNA vaccines, especially that expressing the non-structural protein gene, may be an alternative approach for treatment of individuals chronically infected with HCV.
authors.affiliation: Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yasutomi
mesh_terms: D000818:Animals; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000517:prevention & control* / Q000628:therapy*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000096:biosynthesis / Q000276:immunology*; D015678:Viral Structural Proteins / Q000096:biosynthesis / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D019444:Vaccines, DNA; D017361:Viral Nonstructural Proteins; D015678:Viral Structural Proteins; D014765:Viral Vaccines; D007371:Interferon-gamma
keywords: DNA vaccine; Hepatitis C; Mouse model