Abstract
Hepatitis B virus infection is a serious global health problem and causes life-threatening liver disease. In particular, genotype C shows high prevalence and severe liver disease compared with other genotypes. However, the underlying mechanisms regarding virological traits still remain unclear. This study investigated the clinical factors and capacity to modulate Type I interferon (IFN-I) between two HBV polymerase polymorphisms rt269L and rt269I in genotype C. This report compared clinical factors between rt269L and rt269I in 220 Korean chronic patients with genotype C infections. The prevalence of preC mutations between rt269L and rt269I was compared using this study's cohort and the GenBank database. For in vitro and in vivo experiments, transient transfection using HBV genome plasmid and HBV virion infection using HepG2-hNTCP-C4 and HepaRG systems and hydrodynamic injection of HBV genome into mice tails were conducted, respectively. This report's clinical data indicated that rt269I vs. rt269L was more significantly related to HBV e antigen (HBeAg) negative serostatus, lower levels of HBV DNA and HBsAg, and disease progression. Our epidemiological study showed HBeAg negative infections of rt269I infections were attributed to a higher frequency of preC mutations at 1896 (G to A). Our in vitro and in vivo studies also found that rt269I could lead to mitochondrial stress mediated STING dependent IFN-I production, resulting in decreasing HBV replication via the induction of heme-oxygenase-1. In addition, we also found that rt269I could lead to enhanced iNOS mediated NO production in an IFN-I dependent manner. These data demonstrated that rt269I can contribute to HBeAg negative infections and liver disease progression in chronic patients with genotype C infections via mitochondrial stress mediated IFN-I production.
Highlights
Hepatitis B virus (HBV) infection is a high-risk global health issue leading to severe liver disease
We recently introduced some mutations in the reverse transcriptase (RT) region of Pol related to hepatocellular carcinoma (HCC) from genotype C infected patients [rtM80I, rtN139K/T/H, and rtM204I/V] [20]
It has been reported that most HBV infections in South Korea are due to genotype C [38], which may be a major reason for the lower response of IFN therapy [39] or NA therapy [40], the higher level of disease progression [41], and the higher prevalence of occult infection via vertical transmission [42, 43], observed in Korean chronic hepatitis B (CHB) patients compared to patients in other areas
Summary
Hepatitis B virus (HBV) infection is a high-risk global health issue leading to severe liver disease. Since HBV cccDNA cannot be completely eradicated by nucleot(s)ide analog agents [5], epigenetic regulation via innate immune response modulating agents such as Type I IFN (IFN-I) is necessary for the complete viral clearance from chronic hepatitis B (CHB) patients [6]. In addition to HBV mutations, it has been reported that there are several genotype dependent polymorphisms in HBV RT regions, which are generally defined as having a frequency
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