Mutations of T-Cell Epitopes in the Hepatitis B Virus Surface Gene in Children With Chronic Infection and Hepatocellular Carcinoma

Abstract

Hepatitis B virus (HBV) infection induces an interaction of host immune responses against virus antigen-presenting hepatocytes. The emergence of mutants is a strategy through which the virus can escape host attacks and produce chronic infection. In this study, we aimed to investigate mutations of the human leukocyte antigen-A2-restricted T-cell epitope (TCE) in chronic HBV-infected children. In total, 441 chronic HBV-infected children were longitudinally followed-up every 6 months. They were divided into hepatitis B e antigen (HBeAg) (-) (N = 60) and HBeAg (+) (N = 381) groups according to this seromarker at their enrollment. The HBeAg (+) group was further divided into HBeAg (+/-) (N = 229) and HBeAg (+/+) (N = 152) groups, depending on the occurrence of spontaneous HBeAg seroconversion. Twenty-five children with HBV-related hepatocellular carcinoma (HCC) were also recruited. TCE mutations were examined using the latest serum samples, and serum samples at enrollment were used if TCE mutations were present in the latest serum samples in the seroconverters. HBV genotypes and liver enzymes were also analyzed. The HBeAg (+/+) group had a lower TCE mutation rate (7.9%) than that of the HBeAg (+/-) (29.2%), HBeAg (-) (26.7%), and HCC (28.0%) groups. In the HBeAg (+/-) group, TCE mutations were present before HBeAg seroconversion in 11.9% of the subjects. Those with TCE mutations showed HBeAg seroconversion at an older age (16.1 +/- 5.3 yr vs 12.7 +/- 5.7 yr, P < 0.001) and with higher peak alanine aminotransferase (ALT) levels (median 175 U/L vs 119 U/L, P = 0.03) than those without TCE mutations. TCE mutations tended to be positively associated with HBeAg seroconversion and higher ALT levels in chronic HBV-infected children.