Targeting the Host for New Therapeutic Perspectives in Hepatitis D

Abstract

Hepatitis D virus (HDV) is a small satellite virus of hepatitis B virus (HBV) requiring HBV infection to complete its life cycle. It has been recently estimated that 13% of chronic HBV infected patients (60 million) are co-infected with HDV. Chronic hepatitis D is the most severe form of viral hepatitis with the highest risk to develop cirrhosis and liver cancer. Current treatment is based on pegylated-interferon-alpha which rarely controls HDV infection and is complicated by serious side effects. The development of novel antiviral strategies based on host targeting agents has shown promising results in phase I/II clinical trials. This review summarizes HDV molecular virology and physiopathology as well as new therapeutic approaches targeting HDV host factors.

Keywords: Hepatitis D; antiviral strategy; host factors; liver disease.

Figure 1

Hepatitis D virus (HDV) structure. (A) Schematic representation of HDV viral particle. HDV virion contains an envelope derived from the endoplasmic reticulum, in which are embedded the three forms (S, M and L) of hepatitis B virus (HBV) envelope protein, HBs antigen (HBsAg). HDV genome is a circular single stranded RNA of negative polarity associated to the two forms of delta antigen (L-HDAg and S-HDAg) forming a ribonucleoproteic complex.

Figure 2

HDV life cycle. (1) HDV life cycle starts with HDV virions attachment to heparan sulfate proteoglycans (HSPG), including Glypican 5 (GPC5), at the hepatocyte surface. L-HBsAg pre-S1 region then binds to HBV/HDV specific receptor, the bile acid transporter NTCP. Viral particle enters the cell through endocytosis and viral RNP is freed in the cytoplasm. (2) Both forms of HDAg contain a nuclear localization signal that induces viral RNP translocation to the nucleus. (3) In the nucleus, HDAg mRNA transcription is done by RNA polymerase II. HDAg mRNA is then exported in the cytoplasm where it is translated to produce the small form of HDAg (S-HDAg). (4) During the first step of replication, HDV genomic RNA serves as a template for antigenomic RNA production, probably done by RNA polymerase I. (5) Antigenomic RNA is recognized by RNA polymerase II to produce new genomic RNAs. (6) Antigenomic RNA is edited by ADAR1 enzyme, suppressing S-HDAg stop codon. (7) Edited antigenomic RNA is replicated into genomic RNA, then inducing the transcription of edited HDAg mRNA that is exported in the cytoplasm where it leads to the production of the large form of HDAg (L-HDAg). (8) L-HDAg contains a prenylation site that is farnesylated by a cellular farnesyltransferase before being translocated to the nucleus. (9) Both forms of HDAg interact with newly synthesized genomic RNA to form new viral ribonucleoproteins (RNP) that are exported to the cytoplasm. (10) Viral RNPs interact, through their farnesylated cystein in L-HDAg, with the cytosolic part of HBsAg at the endoplasmic reticulum surface, thus inducing their envelopment. (11) HDV virions are then secreted form the infected cell. The different steps targeted by antiviral treatments are indicated. Represented cell is also infected by HBV, indicated by its cccDNA or its integrated genome, but its life cycle is not depicted.

Figure 3

HDV replication. (1) HDV genome is translocated in the nucleolus. (2) It is then recognized by RNA polymerase I to produce concatemers of linear antigenomic RNAs through a rolling circle mechanism. (3) Ribozyme activity induced the cleavage of antigenomic RNA concatemers in antigenomic RNA monomers. (4) Linear antigenomic RNAs are circularized through an unknown ligation process. (5) Antigenomic RNAs are translocated in the nucleoplasm. (6) They are then recognized by RNA polymerase II to produce concatemers of linear genomic RNAs through a rolling circle mechanism. (7) Ribozyme activity induces the cleavage of genomic RNA concatemers into linear genomic RNA monomers. (8) Linear genomic RNAs are then circularized through an unknown ligation process. (9) Newly synthesized HDV genomic RNAs can be translocated again in the nucleolus for a new round of replication.

Figure 4

Natural history of HBV mono-infection and HDV co- and super-infection.