Unique liver transcriptomics profiles in chronic HBV: intrinsic intrahepatic functional clusters discriminate distinct clinical phases

Since little information is available on the processes in the liver associated with the natural history during chronic HBV infections, we now examined hepatic transcriptomes to identify distinctive gene expression profiles in the HBV clinical phases. We show that the transcriptomes of mild fibrotic, HBV-infected livers were significantly different from those with comorbidities. Across the clinical HBV phases, comparable intrahepatic ISG expression was observed. However, global transcription was most distinctive between the immunotolerant and the immunoactive phases (n=92 genes), followed by the immunotolerant and the HBeAg-negative hepatitis phase (n=71 genes), and the immunotolerant and the inactive carrier phase (n=46 genes). Among these were CD19, TNFRSF13C, granzyme H, and KIR2DS3. Moreover, during these clinical phases, 4 intrinsic functional clusters (IFC) with distinctive transcriptional activity were identified by combined global module analysis. These discriminative clusters contained B-cell and cell cycle-related genes, which were highly expressed in liver during the immunoactive phase; and NK-cell and mitochondria respiration-related genes in the HBeAg-negative hepatitis phase. Our data define distinctive transcriptomes in the liver during HBV clinical phases. We observed important differences between the liver and blood in transcription levels of ISG and cell cycle genes, but, strikingly, also a high degree of overlap in expression patterns of B- and NK-cell genes during the immune active phases. we analyzed a cohort of FFPE biopsies collected from the livers of well-characterized chronic HBV patients (n=74) and archived for up to 30 years. Differential gene expression analysis , global module analysis, and unsupervised clustering analysis were performed by employing the WG-DASL assay on liver transcriptomes from chronic HBV patients with and without concomitant NASH or advanced fibrosis, or between different HBV clinical phases.