Bioinformatic analysis of the hepadnavirus e‐antigen and its precursor identifies remarkable sequence conservation in all orthohepadnaviruses

Abstract

The hepatitis B e-antigen (HBeAg) is a non-particulate secretory protein expressed by all viruses within the family Hepadnaviridae. It is not essential for viral assembly or replication but is important for establishment of persistent infection in vivo. Although the exact mechanism(s) by which the HBeAg manifests chronicity are unclear, the HBeAg elicits both humoral and cell-mediated immunity, down-regulates the innate immune response to infection, as well as functioning as a T cell tolerogen and regulating the immune response to the intracellular nucleocapsid. A bioinformatics approach was used to show that the HBeAg and precursory genetic codes share remarkable sequence conservation in all mammalian-infecting hepadnaviruses, irrespective of host, genotype, or geographic origin. Whilst much of this sequence conservation was within key immunomodulatory epitopes, highest conservation was observed at the unique HBeAg N-terminus, suggesting this sequence in particular may play an important role in HBeAg function.

New insight in the pathobiology of hepatitis B virus infection

“…The HBeAg is translated initially as the PC protein P25, and then undergoes cleavage of the N-terminal signal sequence in the ER/Golgi complex, producing a 22 kDa protein (P22), which can either undergo further processing to form the secreted 17 kDa HBeAg (P17), or traffic to the cytosol where it remains localised 11. Except for a 10-amino-acid N-terminal extension, which is highly conserved in all orthohepadnaviruses and contains a putative toll-interleukin-1 receptor (TIR) domain,12 HBeAg shares significant homology with the core protein (P21), which is translated using the core AUG codon of the same ORF 13…”

The Hepatitis B e antigen (HBeAg) targets and suppresses activation of the Toll-like receptor signaling pathway

“…Although the majority of this signal-cleaved product is secreted, between 20% and 30% [14] of the mature protein is retained in the cytoplasm, although no specific role has been ascribed to the cytosol-localized form of HBeAg [15]. Interestingly, the HBeAg precursory genetic codes share remarkable sequence conservation in all mammalian-infecting hepadnaviruses, irrespective of host, genotype, or geographic origin [29]. Alternatively, hepatitis B core antigen (HBcAg) is a truncated protein highly homologous to HBeAg, sharing an open reading frame [6].…”

Assessment of differences in the conformational flexibility of hepatitis B virus core‐antigen and e‐antigen by hydrogen deuterium exchange‐mass spectrometry

“…7 While the role of e-antigen in regulating the immune system is only partially understood, 8,9 its high evolutionary conservation in the Hepadnaviridae suggests the importance of its function. 10 The core-antigen protein is comprised of a 149-residue assembly domain and a 34-residue C-terminal arginine-rich domain [ Fig. 1(A)].…”