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The G1862T mutation, which occurs most frequently in subgenotype A1 of the hepatitis B virus (HBV), results in a valine to phenylalanine substitution at the -3 position of the signal peptide cleavage site at the amino end of the precore/core (preC/C) precursor protein. The objective of this study was to functionally characterize the G1862T mutation relative to its wild-type counterpart in subgenotype A1. Huh7 cells were transfected with subgenotype A1 replication-competent plasmids, with and without G1862T. Secretion of HBsAg and HBeAg, preC/C/HBeAg expression in the secretory pathway, activation of the unfolded protein response (UPR) and subsequent activation of apoptosis were monitored. The introduction of G1862T did not affect HBsAg expression. Cells transfected with the G1862T subgenotype A1 plasmid showed decreased expression of intracellular HBcAg and of nuclear preC/C/HBeAg and extracellular HBeAg, when compared to cells transfected with its wild-type counterpart as a result of the accumulation of the mutant protein in the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment (ERGIC) . This accumulation of preC/C/HBeAg protein in the ER led to the earlier activation of the three UPR pathways, but not to an increase in apoptosis. Therefore, it is evident that the presence of G1862T in subgenotype A1 does not completely abolish HBeAg expression, but affects the rate of HBeAg maturation, its passage through the secretory pathway and activation of the UPR. Increase in ER stress can result in liver damage, which has been shown to be a contributing factor to hepatocarcinogenesis and may explain why G1862T is frequently found in subgenotype A1 from liver disease patients.

Expression of wild-type or G1862T mutant HBe antigen of subgenotype A1 of hepatitis B virus and the unfolded protein response in Huh7 cells