A review on hepatitis D: From virology to new therapies

Abstract

Hepatitis delta virus (HDV) is a defective virus that requires the hepatitis B virus (HBV) to complete its life cycle in human hepatocytes. HDV virions contain an envelope incorporating HBV surface antigen protein and a ribonucleoprotein containing the viral circular single-stranded RNA genome associated with both forms of hepatitis delta antigen, the only viral encoded protein. Replication is mediated by the host cell DNA-dependent RNA polymerases. HDV infects up to72 million people worldwide and is associated with an increased risk of severe and rapidly progressive liver disease. Pegylated interferon-alpha is still the only available treatment for chronic hepatitis D, with poor tolerance and dismal success rate. Although the development of antivirals inhibiting the viral replication is challenging, as HDV does not possess its own polymerase, several antiviral molecules targeting other steps of the viral life cycle are currently under clinical development: Myrcludex B, which blocks HDV entry into hepatocytes, lonafarnib, a prenylation inhibitor that prevents virion assembly, and finally REP 2139, which is thought to inhibit HBsAg release from hepatocytes and interact with hepatitis delta antigen. This review updates the epidemiology, virology and management of HDV infection.

Keywords: Chronic hepatitis; Epidemiology; Hepatitis delta management; Hepatitis delta virus; Treatment; Virus life cycle.

Graphical abstract

Fig. 1

Structure of HBV and HDV virions. Both viruses use HBV surface proteins (S-, M- and L-HBsAg) for their assembly. HBV icosahedral capsid is formed by multimerisation of its core protein (HBcAg) and contains one copy of the viral partially double-stranded DNA genome (or relaxed circular DNA, rcDNA) and the viral polymerase. HDV virions contain one copy of the viral circular, single-stranded RNA genome (that has 70% of sequence complementarity, allowing its folding into a rod-like structure), associated with both forms of its only protein (large and small delta antigen or S- and L-HDAg), forming the viral ribonucleoprotein (RNP).

Fig. 2

HDV life cycle. HDV entry (step 1) is mediated by a first attachment step, resulting from viral interaction with HSPGs, and later specific interaction of L-HBsAg with the viral receptor, NTCP. This step is inhibited by Myrcludex B. The viral RNP is then transported to the nucleus (step 2) where it releases the viral genome that serves as template to transcription of HDV mRNA (step 3), from which HDAg is translated (step 4). Replication of viral RNA (step 5) is mediated by cellular DNA-dependent RNA polymerases in the presence of S-HDAg, through a rolling-circle mechanism, with formation of multimeric and antigenomic RNA intermediates. During replication, antigenomic RNA can be edited by ADAR1 (step 6), leading to the expression of L-HDAg molecules (as detailed in Fig. 3). Farnesylation of L-HDAg (step 7), a step inhibited by lonafarnib, is necessary for regulation of replication and viral assembly. The newly formed HDV RNPs are assembled in the nucleus (step 8), exported and then enveloped by HBV surface glycoproteins (step 9) through the interaction of farnesylated L-HDAg with HBsAg. HDV virions are thought to be secreted through the Golgi (step 10) in parallel with HBV SVPs. Although the precise mechanism of action of REP 2139 is not fully characterized, it has been shown not to interfere with viral entry of HBV or HDV but appears to affect HDV secretion by inhibiting secretion of HBsAg and also potentially by interacting with HDAg. The exact mechanism of action of interferons (both alpha and lambda) is not represented, as it is still not fully known (although it is believed to involve an inhibition of viral RNA replication). ADAR1, adenosine deaminase acting on RNA 1; AG, antigenome; ER, endoplasmic reticulum; G, genome; HBV, hepatitis B virus; HDV, hepatitis B virus; HSPGs, heparan sulfate proteoglycans; NTCP, sodium taurocholate co-receptor peptide; RNP, ribonucleoprotein; SVPs, subviral particles.

Fig. 3

Differential expression of S- and L-HDAg as a consequence of antigenome RNA editing by ADAR-1. The HDV antigenomic RNA has one single open reading frame from which the two isoforms of HDAg are expressed. Adenosine deaminase acting on RNA-1 (ADAR1) catalyses editing of the amber/W site on the antigenomic HDV RNA and adenosine 1012 is converted to inosine. After replication and mRNA transcription, the original stop codon (AUG, terminating the synthesis of S-HDAg) is converted into UGG, coding for a tryptophan (Trp) residue and allowing translation to proceed until the next stop codon, which results in the addition of 19 amino acids (L-HDAg).