Liver Biopsy Clinical Trial
Official title:
HBV DNA Replication in Hepatocytes in HBV and HDV Co-infection
Study the content of the HBV DNA in liver biopsy in the patients with the Chronic Hepatitis Delta in absence of the HBV DNA in the blood plasma
Investigators interpreted the data of several researchers that studied suppression of the HBV
DNA replication in the Delta infection within this article. Co-infection and superinfection
of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV
replication in both patients as well as animals and cell models. The mechanisms underlying
this suppression were not fully studied before.
Jaw-Ching Wu et al. described the suppression of HBV DNA replication during HBV and HDV
co-infection for the first time in 1991. The results of studies in the liver experimental
models HuH-7 clearly demonstrated that one delta HDV antigen can suppress the expression of
HBV RNA.
Dulce Alfaiate et al. conducted studies on the experimental models proving that HBV
replication markers, including HBeAg, total HBV DNA and pregenomic RNA were significantly
reduced after superinfection with HDV which confirming the effect of HDV on HBV. But thereby,
the levels of circularly covalently closed levels of HBV DNA (cccDNA) and HBsAg were not
decreased. At the peak of HDV-RNA accumulation and appearance of the interference in HBV
replication, a strong I type IFN response was observed with highly induced genes stimulated
by the interferon, RSAD2 (Viperin) and IFI78 (MxA). Both mono- and superinfected dHepaRG
cells maintained strong intracellular replication of HDV, which was accompanied with the
strong secretion of infectious HDV virions.
The following analysis of the data in the experimental studies by Zhenfeng Zhang et al.
proved that the HDV virus activated strongly IFN-β and IFN-λ in the hepatocyte cell lines.
The active HDV replication induces the IFN-β/λ response. Unlike hepatitis B virus, hepatitis
D virus infection causes a strong IFN-β/λ response in the innate immunocompetent cell lines.
The activated IFN did not suppress replication of hepatitis D virus in vitro, which
indicatesthat Delta hepatitis virus is resistant to the self-induced innate immune responses
and therapeutic treatment for IFN.
According to the authors, this stimulation of the synthesis of endogenous IFN-β and IFN-λ
inside the hepatocyte by the HDV virus caused suppression of the HBV virus replication.
The following study, conducted Paolo Pugnale et al., in Huh-7 human hepatoma cells
demonstrates that HDV can disrupt the IFN-α-stimulated JAK-STAT signaling pathway (a
mediating protein ensuring cell response to the signals from the interleukin receptors and
growth factors). The mechanism adopted by HDV to interfere with IFN-α/β signaling is based on
inhibition of the tyrosine phosphorylation of STAT1, STAT2 and Tyk2 receptor-bound kinase
without reducing expression levels of the IFN receptor subunits or other components in the
signaling cascade. These results indicate that the HDV virus develops a strategy to
counteract the actions of I type IFN. This study may be useful for a better understanding of
the observed resistance to IFN in the chronic patients with the Chronic Hepatitis Delta and
may provide the useful data for defining new strategies for antiviral intervention.
However, it should be noted that KatashibaY. in his research indicates that IFN is mainly
stimulated in case of infection with the DNA-containing viruses, while IL-12 induction
predominates in case of the RNA-containing infections. Since HDV consists of a
single-stranded RNA molecule, it is not expected to stimulate IFN.
Given the above stated disagreements in the results of the authors' studies, Investigators
decided to examine the patients with the Chronic Hepatitis Delta when the HBV DNA was not
detected in the blood during examination by PCR.
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