Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan.
Vaccine. 2013 Dec 5;31(50):5968-74. doi: 10.1016/j.vaccine.2013.10.037. Epub 2013 Oct 19.
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.
大多数感染丙型肝炎病毒 (HCV) 的人都会发展为慢性肝炎，在某些情况下会进展为肝硬化，最终发展为肝细胞癌。虽然已经研究了针对 HCV 感染进行性疾病状态的各种免疫疗法，但针对这种病原体的预防性或治疗性疫苗仍未问世。在这项研究中，我们构建了一种表达 HCV 结构蛋白 (CN2)、非结构蛋白 (N25) 或空质粒 DNA 的 DNA 疫苗作为对照，并评估了它们作为 HCV 候选疫苗在 C57BL/6 和新型基因修饰 HCV 感染模型 (HCV-Tg) 小鼠中的功效。在 CN2 或 N25 DNA 疫苗免疫的 C57BL/6 小鼠中观察到针对几种 HCV 结构和非结构蛋白的强烈细胞免疫反应，其特征是细胞毒性和干扰素-γ (IFN-γ) 的产生，但在空质粒 DNA 给药的小鼠中没有观察到。这些 DNA 疫苗的治疗效果也在条件性在肝脏中表达 HCV 蛋白的 HCV-Tg 小鼠中进行了检查。尽管在 HCV-Tg 小鼠中观察到细胞免疫反应降低，但在给予 N25 DNA 疫苗的小鼠中 HCV 蛋白的表达显著降低，而在给予空质粒 DNA 的小鼠中则没有。此外，CD8(+) 和 CD4(+) T 细胞都需要减少肝脏中的 HCV 蛋白。我们发现 N25 DNA 疫苗与空质粒 DNA 相比改善了肝脏的病理变化。因此，这些 DNA 疫苗，特别是表达非结构蛋白基因的疫苗，可能是治疗慢性 HCV 感染个体的一种替代方法。
