Editorial: HBV-the naked truth?

In a recent issue of AP&T, Jiang et al 1 described the characterisation of an envelope deletion variant of hepatitis B virus (HBV) isolated from a patient. The authors showed that the deleted amino acid domain 25‐39 of PreS1 contributes to viral morphogenesis and affects hepatitis B surface antigen (HBsAg) secretion. However, what is the role of the deletion variant virus produced in the patient? It is well known that HBV particles contain a partially double stranded circular DNA encapsidated by 180‐240 copies of the hepatitis B core antigen (HBcAg) covered by a lipid‐bilayer outer shell containing three versions of the HBsAg (small, middle and large2;). The large HBsAg (LHBsAg) is responsible for viral attachment and entry using the Na+‐taurocholate cotransporting polypeptide (NTCP) receptor on hepatocytes.3 Antibodies to the three forms of HBsAg (SHBsAg, MHBsAg, LHBsAg) are the classical antibodies that ostensibly neutralise the viral particle. In contrast the dominant antibody response to HBV is, as with many viral infections, directed at the capsid protein hepatitis B core antigen (HBcAg). The antibodies to HBcAg, anti‐HBc, are generally considered to have no biological effect during the infection as this antigen has not been identified on the surface of the virus or the infected cell. So, how may B cells come in contact with a subcellular antigen, apart from lysis, leakage or disruption of infected cells? The current paper showed that a mutant, patient‐derived, HBV particle may not in all cases be completely covered by the envelope. In fact, a portion of HBV particles are partially naked, meaning that part of the viral exterior is actually HBcAg. The particles obviously appear in vivo but do not seem to be infectious, as the NTCP binding site within the PreS1 domain of the LHBsAg protein has been disrupted. This raises two questions: what is their role in infection and how is the deletion variant selected? This deletion variant was shown to be non‐infectious: this would indeed be a detrimental deletion variant that should only be expressed from a defective cccDNA or an integrated gene fragment. The main question is, what are the implications of this finding? Is this merely an interesting epiphenomenon that is of no signficance or is there more to learn and discover about partially naked HBV particles? Theoretically, they should be rapidly”neutralized” and cleared by the existing circulating high levels of anti‐HBc (Figure 1). In fact, the presence of the high levels of anti‐HBc may even be amplified by the presence of partially enveloped HBV particles, as this would shuttle HBcAg to the antigen presentation pathway.4 Is there any other functional significance of these particles? The authors propose that these particles may help to block PreS1 and PreS2 antibodies not affected by the deletion. However, this would require a substantial level of production of these particles. Finally, it is likely that the high levels of anti‐HBc in the sera would rapidly clear these particles from the circulation, whereby their ability to block PreS1 and PreS2 antibodies may be limited. Or can these particles still bind PreS1 and PreS2 antibodies when bound by anti‐HBc? In that case the anti‐HBc response may help to clear PreS1 and PreS2 antibodies. The naked truth about these interesting newly observed in vivo partially enveloped and partially naked, HBV remains elusive and points to gaps in our understanding of hepatitis B replication and the looming complexity of potential cures.

Figure 1

Schematic description of the possible function and limitations, of the preS1‐deletion variant