Quadruple mutation GCAC1809-1812TTCT leads to a better prognosis by decreasing HBV-mediated fibrogenic activity

Background and Aims HBV mutations occur regularly and are relevant for the course of infection, for example the quadruple mutation GCAC1809-1812TTCT (TTCT), that coexists with the basal core promoter double mutation (BCP) and is associated with significantly lower HBV DNA levels and an inactive carrier status and thus a better prognosis. Exploring the relationship between mutations and liver disease progression is essential for effective clinical treatment of HBV patients.

Methods Supergenomic constructs+/- BCP and TTCT mutation were used to analyze their transcriptional activity via reporter gene assays, western blots and RT-qPCR analysis. For measuring reactive oxygen species we used oxyblot and flow cytometry. To investigate the influence of the presence or absence of TTCT on kinase activity, kinome profiling was performed. Finally, the amount/distribution of Hbx was determined by immunofluorescence microscopy ([Abb. 1]).

Abb. 1  

Results The TTCT mutation in HBx and core leads to a slightly higher induction of the Nrf2/ARE-dependently regulated gene NQO1 as well as lower ROS levels compared to the BCP mutation without TTCT or the wild-type. In addition, the presence of the TTCT mutation showed downregulation of the serine/threonine kinases PKA, PKG2, and PRKX, whereas the BCP mutation without TTCT enhances effects of wild-type HBV.

Conclusion TTCT leads to a better prognosis by inducing the expression of cytoprotective genes and downregulation of those major kinases that contribute to liver fibrosis.

Publikationsverlauf

Artikel online veröffentlicht:
28. August 2023