Young K G, Haq K, MacLean S, Dudani R, Elahi S M, Gilbert R, Weeratna R D, Krishnan L
Ottawa Hospital Research Institute, Ottawa, ON, Canada.
National Research Council Canada, Ottawa, ON, Canada.
J Viral Hepat. 2018 Jun;25(6):649-660. doi: 10.1111/jvh.12856. Epub 2018 Feb 21.
Hepatitis C virus (HCV) chronically infects 2%-3% of the world's population, causing liver disease and cancer with prolonged infection. The narrow host range of the virus, being restricted largely to human hepatocytes, has made the development of relevant models to evaluate the efficacy of vaccines a challenge. We have developed a novel approach to accomplish this by generating a murine hepatoma cell line stably expressing nonstructural HCV antigens which can be used in vitro or in vivo to test HCV vaccine efficacies. These HCV-recombinant hepatoma cells formed large solid-mass tumours when implanted into syngeneic mice, allowing us to test candidate HCV vaccines to demonstrate the development of an HCV-specific immune response that limited tumour growth. Using this model, we tested the therapeutic potential of recombinant anti-HCV-specific vaccines based on two fundamentally different attenuated pathogen vaccine systems-attenuated Salmonella and recombinant adenoviral vector based vaccine. While attenuated Salmonella that secreted HCV antigens limited growth of the HCV-recombinant tumours when used in a therapeutic vaccination trial, replication-competent but noninfectious adenovirus expressing nonstructural HCV antigens showed overall greater survival and reduced weight loss compared to non-replicating nondisseminating adenovirus. Our results demonstrate a model with anti-tumour responses to HCV nonstructural (NS) protein antigens and suggest that recombinant vaccine vectors should be explored as a therapeutic strategy for controlling HCV and HCV-associated cancers.
丙型肝炎病毒（HCV）长期感染全球2%-3%的人口，随着感染时间延长会导致肝脏疾病和癌症。该病毒的宿主范围狭窄，主要局限于人类肝细胞，这使得开发相关模型来评估疫苗疗效成为一项挑战。我们开发了一种新方法来实现这一目标，即生成一种稳定表达HCV非结构抗原的小鼠肝癌细胞系，可用于体外或体内测试HCV疫苗疗效。这些HCV重组肝癌细胞植入同基因小鼠后会形成大的实体瘤，使我们能够测试候选HCV疫苗，以证明产生了限制肿瘤生长的HCV特异性免疫反应。利用该模型，我们基于两种根本不同的减毒病原体疫苗系统——减毒沙门氏菌和基于重组腺病毒载体的疫苗，测试了重组抗HCV特异性疫苗的治疗潜力。在治疗性疫苗试验中，分泌HCV抗原的减毒沙门氏菌可限制HCV重组肿瘤的生长，而表达非结构HCV抗原的具有复制能力但无感染性的腺病毒与无复制能力且不扩散的腺病毒相比，总体生存率更高，体重减轻更少。我们的结果证明了一种对HCV非结构（NS）蛋白抗原有抗肿瘤反应的模型，并表明应探索重组疫苗载体作为控制HCV及HCV相关癌症的治疗策略。
