Influence of vitamin D on the hepatitis B virus life cycle in different genotypes
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Abstract
In spite of a very effective vaccine being available since the 1980s, over 240 million people worldwide suffer from chronic HBV (Hepatitis B virus) infection. HBV, belonging to the family Hepadnaviridae, is transmitted via body fluids and blood transfusions and infects the human liver. HBV is classified into eight different genotypes with a genome-variety of > 8%. The genotypes are regionally distributed and differ in their progression of disease with regard to the response to antivirals and the development of HCC (hepatocellular carcinoma) (Tian and Jia, 2016). Some clinical observations indicate that in chronic HBV-infected patients the virus load varies seasonally due to the triggering factor vitamin D, which is produced in the skin by the exposure of sun (Farnik et al., 2013). Infected hepatocytes release, in addition to the virus itself, huge amounts of SVPs (subviral particles), which consist of the viral surface proteins (HBsAg) and form spheres and filaments. While the VPs (virions) and filaments are released ESCRT (endosomal sorting complexes required for transport) -dependently via MVBs (multi vesicular bodies), the secretion of the spheres occurs via the ER-/Golgi-pathway (Jiang et al., 2015). The aim of this project was to analyze whether vitamin D has a direct effect on the HBV life cycle in the different genotypes and to determine a potential mechanism of the inhibition in cell culture systems.
For analyzing the influence, six different vitamin D analogs were tested in stably and transiently HBV expressing hepatoma cell lines and PHHs (primary human hepatocytes). The investigation of the cell culture supernatant and cell lysates reveals an altered ratio of viral components intra- and extracellularly, presenting evidence for a reduced release of the virus upon vitamin D treatment. Hereby, the viral transcripts were not influenced. Furthermore, vitamin D leads to a diminished expression of the viral factor α-Taxilin. The results indicate that α-Taxilin, which is crucial for the MVB-dependent release of HBV (Hoffmann et al., 2013), is causative for the observed effect of vitamin D. The comparative analysis of the HBV genotypes showed differences in the reduction on release of HBV upon vitamin D treatment. Here, the HBV genotype C did not react at all on vitamin D treatment. It is assumed that the treatment with vitamin D is a suitable tool for the further characterization of the HBV genotypes, as hitherto only limited in vitro analyses were performed.
The presented work reveals the impact on the analysis of the influence of vitamin D on the HBV life cycle and the comparative characterization of the HBV genotypes.