Impact of HBV and HCV Sequence Diversity on the CD8 T Cell Immune Response

当免疫应答的重要靶标在循环分离株之间不同时，病原体如HBV和HCV的固有序列多样性可代表免疫控制的障碍。据充分记载，HCV的宿主内进化导致抗病毒CD8 T细胞免疫应答的失败。最近，有证据表明HBV也能够适应CD8 T细胞选择压力。然而，与HCV相反，已经强调HBV基因组的可塑性更受重叠阅读框的存在的限制。因此，HBV对HLA I类相关选择压力的适应过程的总体程度在很大程度上是不清楚的。虽然有效的预防性疫苗是针对HBV，逃逸突变的选择将是相关的治疗性疫苗接种策略，当自体病毒不再是由免疫应答的目标。本研究将分析HBV对CD8 T细胞免疫压力的适应程度和机制。对于HCV，除了宿主内进化之外，循环分离株之间的固有病毒序列多样性可能导致缺乏保护性免疫。这在高危人群中最为明显，例如反复暴露于遗传上不同的分离株的注射毒品（PWID）人群。HCV的遗传变异性与预防性免疫策略相关，因为任何选择的疫苗抗原序列在暴露时都可能与病毒序列不同。针对表位的多种变体的CD8 T细胞在这种情况下可能是有益的。在这里，交叉反应性CD8 T细胞的频率，功能和分子特征将进行研究，并在B型肝炎和丙型肝炎的背景下，他们的相关性将得到解决。

The inherent sequence diversity of pathogens such as HBV and HCV can represent an obstacle to immune control when important targets of the immune response differ between circulating isolates. It is well documented that intra-host evolution of HCV contributes to failure of the antiviral CD8 T cell immune response. Recently, evidence emerged that HBV is also able to adapt to CD8 T cell selection pressure. In contrast to HCV, however, it has been highlighted that the plasticity of the HBV genome is more constrained by existence of overlapping reading frames. Accordingly, the overall extent of the adaptation process of HBV to HLA class I-associated selection pressure is largely unclear. Although an effective prophylactic vaccine is available against HBV, selection of escape mutations would be relevant for therapeutic vaccination strategies, when the autologous virus is not targeted by the immune response anymore. In this project the extent and mechanisms of adaptation of HBV to CD8 T cell immune pressure will be analyzed. For HCV, beyond intra-host evolution, the inherent viral sequence diversity between circulating isolates likely contributes to lack of protective immunity. This is most evident in high-risk groups such as people how inject drugs (PWID), being repeatedly exposed to genetically distinct isolates. The genetic variability of HCV is relevant for prophylactic immunization strategies, because any chosen vaccine antigen sequence will likely differ from the viral sequence upon exposure. CD8 T cells directed against multiple variants of an epitope may be beneficial in this setting. Here, the frequency, function and molecular characteristics of cross-reactive CD8 T cells will be studied and their relevance in the context of hepatitis B and hepatitis C will be addressed.