Characterization of Genotype-Specific Carboxyl-Terminal Cleavage Sites of Hepatitis B Virus e Antigen Precursor and Identification of Furin as the Candidate Enzyme

Abstract

Hepatitis B e antigen (HBeAg) is a secreted version of hepatitis B virus (HBV) core protein that promotes immune tolerance and persistent infection. It is derived from a translation product of the precore/core gene by two proteolytic cleavage events: removal of the amino-terminal signal peptide and removal of the carboxylterminal arginine-rich sequence. Four RXXR motifs are present at the carboxyl terminus of the HBeAg precursor, with the first two fused as 151 Approximately 2 billion people worldwide have been exposed to hepatitis B virus (HBV), and 350 million of them remain chronically infected. The long-term consequences of HBV infection include liver cirrhosis and hepatocellular carcinoma (21). The risk of developing chronic HBV infection correlates inversely with the age of transmission. In areas where HBV infection is endemic, such as China where over 10% of people are chronic carriers of the virus, HBV is transmitted both horizontally during early childhood and vertically from hepatitis B e antigen (HBeAg)-positive mothers during birth (68). In countries of intermediate HBV incidence such as South Africa, infection is acquired primarily horizontally during early childhood (28). In Western countries, HBV is transmitted mostly by drug abuse or unprotected sex during adulthood, and the majority of carriers will recover from the acute infection. In this regard, HBeAg is implicated as a major viral factor contributing to chronic infection following neonatal transmission (41).HBeAg was discovered by Magnius and Espmark over 30 years ago as a new serological marker for HBV infection (38), supplementing the then available assays for HBcAg (HBV core antigen or core protein) and HBsAg (HBV surface antigen or envelope protein). Soon after its discovery, the presence of HBeAg was found to correlate with liver diseases, whereas the loss of HBeAg followed by the rise of corresponding antibody (anti-HBe) was associated with normalization of liver function (22,65). Later studies further revealed a correlation of HBeAg with high viremia titer and anti-HBe with reduced viral load.

Impairment of Hepatitis B Virus Virion Secretion by Single-Amino-Acid Substitutions in the Small Envelope Protein and Rescue by a Novel Glycosylation Site

“…Huh7 human hepatoma cells were seeded in six-well plates and transfected with LT1 (Mirus) as described previously (7,15,35). Each well of the six-well plates received 2 g HBV DNA and 5 ng of cDNA encoding secreted alkaline phosphatase (SEAP) to serve as a control for transfection efficiency.…”

The supercritical CO2 extract from the skin of Bufo bufo gargarizans Cantor blocks hepatitis B virus antigen secretion in HepG2.2.15 cells

“…Moreover, SCE-BC had greater inhibitory activity with respect to HBeAg than to HBsAg. Since HBeAg promotes immune tolerance and persistent infection during HBV infection (24), the present results suggest that immune tolerance induced by HBeAg might be overcome by SCE-BC. Therefore, SCE-BC warrants further investigation.…”

Expression and Clinical Significance of Myeloid Derived Suppressor Cells in Chronic Hepatitis B Patients

“…Secreted proteins HBeAg were tolerogens, which were not only inhibit T helper 1-type (Th1) immune cells but also exhaust cytokines helped Th1 (Milich et al, 2003;Ito et al, 2009;Revill et al, 2010). But, it seemed very friendly with T helper 2-type (Th2) immune cells, activating the Th2 cells and promoting production of Th2 related cytokine.…”