Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene.

Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2. Repression of these enhancers has been reported to be one of the main mechanisms of HBV inhibition. Moreover, in a previous study, it has been demonstrated that alpha interferon (IFN-alpha)-inducible MxA protein inhibits HBV replication. HDV encodes two proteins, p24 and p27. p27 was shown to activate several heterologous promoters, including HBV promoters. In an attempt to analyse the mechanisms of HBV inhibition by HDV, the question was raised whether HDV proteins could act directly by repressing HBV enhancers, and/or indirectly by activating the MxA gene. This issue was addressed in a co-transfection model in Huh-7 cells, using p24- or p27-expressing plasmids along with Enh1, Enh2, HBV and MxA promoter-luciferase constructs. Enh1 and Enh2 were strongly repressed, by 60 and 80 % and 40 and 60 %, by p24 and p27, respectively. In addition, p27 was responsible for threefold activation of the MxA promoter and potentiation of IFN-alpha on this promoter. MxA mRNA quantification and a virus yield reduction assay confirmed these results. In conclusion, this study shows that HDV proteins inhibit HBV replication by trans-repressing its enhancers and by trans-activating the IFN-alpha-inducible MxA gene.

Hepatitis delta virus genotypes I and II cocirculate in an endemic area of Yakutia, Russia.

Currently, three genotypes of hepatitis delta virus (HDV) are described. The most common, genotype I, has a worldwide distribution; in contrast, genotype II has been found previously only in Japan and Taiwan, while genotype III is found exclusively in South America. Considering the high prevalence of HDV in Northern Siberia (Russia), restriction fragment length polymorphism (RFLP) was used to analyse HDV genotypes from 29 infected patients living in Yakutia. Of these isolates, 11 were characterized by partial nucleotide sequencing and two isolates were completely sequenced. Phylogenetic inference methods included maximum parsimony, maximum likelihood and distance analyses. A restriction pattern consistent with HDV genotype I was found in 14 samples, while the remaining 15 showed a different restriction pattern, inconsistent with any known genotype. Five Yakutian HDV isolates with the type I restriction pattern were sequenced and confirmed to be affiliated with genotype I, although the phylogenetic results indicate that they were heterogeneous and did not cluster together. Sequencing of eight isolates with the new RFLP pattern revealed that these isolates were most closely related to HDV genotype II. In contrast to HDV Yakutian genotype I sequences, all of these type II sequences formed a well-defined clade on phylogenetic trees. Comparison of clinical presentations during hospitalization between patients infected with HDV type I (n=14) and type II (n=15) did not reveal any differences in the severity of infection. These data indicate that the distribution of genotype II is not restricted to Taiwan or Japan, but spreads over Northern Asia, appearing in the native population of Yakutia. Type II Yakutian strains appeared to form a well-defined subclade and could be associated with severe chronic hepatitis in this area.

Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades.

Hepatitis D virus (HDV) is a satellite of hepatitis B virus (HBV) for transmission and propagation and infects nearly 20 million people worldwide. The HDV genome is a compact circular single-stranded RNA genome with extensive intramolecular complementarity. Despite its different epidemiological and pathological patterns, the variability and geographical distribution of HDV are limited to three genotypes and two subtypes that have been characterized to date. Phylogenetic reconstructions based on the delta antigen gene and full-length genome sequence data show an extensive and probably ancient radiation of African lineages, suggesting that the genetic variability of HDV is much more complex than was previously thought, with evidence of additional clades. These results relate the geographic distribution of HDV more closely to the genetic variability of its helper HBV.