Impact of HBV-HCV coinfection on virus-specific cytotoxic T-cell responses and viral persistence

由于传播途径相同，以及全球乙肝病毒和丙型肝炎病毒的高发病率，两种病毒的混合感染很常见。临床研究表明，乙肝病毒-丙型肝炎病毒混合感染的病程不同于单一感染：1.随着肝硬变和肝细胞癌的快速、频繁发展，乙肝病毒-丙型肝炎病毒混合感染的临床病程更为严重。2.混合感染导致病毒相互作用，即病毒的相互抑制。一种可能的机制是调节T细胞介导的免疫反应，因为获得性免疫反应在乙型肝炎病毒和丙型肝炎病毒的发病机制、临床病程和复制控制中起着关键作用。此外，有效的T细胞反应是持续消除乙肝病毒和丙型肝炎病毒的先决条件。因此，免疫调节过程对于病毒持久性的发展和治疗靶点至关重要。因此，本项目的目的是验证与单一感染相比，乙肝病毒-丙型肝炎病毒混合感染是否影响T细胞介导的免疫反应。为此，将建立一种新的乙肝病毒-丙型肝炎病毒共感染的免疫细胞培养体系。此外，还将研究乙肝病毒-丙型肝炎病毒混合感染对作为乙肝病毒持续存在的重要储存库的cccDNA的影响。在结构蛋白和HepaRG细胞培养系统中含有突变的乙肝病毒结构将被使用。

Due to shared routes of transmission and due to high global incidences of HBV and HCV, coinfections with both viruses are common. Clinical studies have demonstrated that the course of HBV-HCV coinfection differs from monoinfections: 1. HBV-HCV coinfection shows a more severe clinical course with rapid and frequent development of liver cirrhosis and hepatocellular carcinoma (HCC). 2. Coinfection leads to viral interaction in terms of a reciprocal viral suppression. A possible mechanism is the modulation of the T-cell mediated immune response, as the adaptive immune response plays a key role for the pathogenesis, the clinical course, and the control of replication of HBV and HCV. Furthermore, an efficient T-cell response is a prerequisite for a sustained elimination of HBV and HCV. As a consequence, immunmodulatory processes are of utmost importance for the development and therapeutic targeting of viral persistence. Therefore, the aim of this project is to validate whether HBV-HCV coinfection influences the T-cell mediated immune response in comparison to monoinfection. For this purpose a novel immunological cell culture system of HBV-HCV coinfection will be established. In addition, the impact of HBV-HCV coinfection on cccDNA, an important reservoir of HBV persistence will be studied. HBV constructs harboring mutations within the structural proteins as well as the HepaRG cell culture system will be employed.