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Lars Magnius, John Taylor, William S. Mason, Camille Sureau, Paul Dény and Helene Norder
A summary of this ICTV Report chapter has been published as an ICTV Virus Taxonomy Profile article in the Journal of General Virology, and should be cited when referencing this online chapter as follows:
Magnius, L., Taylor, J., Mason, W.S., Sureau, C., Dény, P., Norder, H., and ICTV Report Consortium. 2018, ICTV Virus Taxonomy Profile: Deltavirus, Journal of General Virology, 99: 1565–1566.
Hepatitis delta virus (HDV), the only member of the only species (Hepatitis delta virus) in the genus Deltavirus, is a unique human pathogen. Its genome is similar to that of viroids with circular RNA, but encodes a protein, hepatitis delta antigen (HDAg). HDAg occurs in two forms, small HDAg (S-HDAg) and large HDAg (L-HDAg), both of which have unique structural and regulatory functions. HDV is hepatotropic and uses host RNA polymerase II in hepatocyte nuclei to replicate via a double-rolling circle mechanism of RNA synthesis. Newly synthesized linear RNA molecules are circularized by autocatalytic cleavage activity and ligation. HDV requires the envelope proteins of the helper virus, human hepatitis B virus (HBV) (family Hepadnaviridae) for assembly and release of infectious particles.
Table 1.Deltavirus. Characteristics of the genus Deltavirus.
hepatitis delta virus clade 1 (M21012), species Hepatitis delta virus, genus Deltavirus
36–43 nm in diameter with an outer envelope containing all three envelope proteins of the helper hepatitis B virus and an inner ribonucleoprotein consisting of HDV RNA, S- and L-HDAg proteins
Circular negative-sense single-stranded RNA of about 1.7 kb
Rolling circle mechanism of RNA-directed RNA synthesis by host RNA polymerase II and autocatalytic cleavage and re-cyclization in the nucleus
mRNA species for S- and L-HDAg proteins
Hepatitis B virus-infected humans are the only known natural hosts
One genus including a single species
Virions of HDV are approximately spherical, with an average diameter of 36–43 nm and lack visible surface projections (Figure 1.Deltavirus). Virions have an outer envelope containing lipid and all three envelope proteins of the co-infecting helper human HBV, a member of the Hepadnaviridae family; woodchuck hepatitis virus can also act as a helper in laboratory infection of woodchucks (Ponzetto et al., 1984). The HDV-encoded protein(s), known as HDAg, exists in two forms: small S-HDAg (p24) and L-HDAg (p27). L-HDAg differs from S-HDAg by a 19 amino acid C-terminal extension (Chao et al., 1990). The HDV virion has an inner ribonucleoprotein comprising approximately 70 copies of variable amounts of S-HDAg and L-HDAg in close association with HDV RNA (Gudima et al., 2007). Nucleocapsid symmetry has not been determined. Nucleocapsids can be released by treatment of virions with non-ionic detergent and dithiothreitol.
Figure 1.Deltavirus. Schematic representation of a particle of hepatitis delta virus.
Virions have a buoyant density in CsCl of about 1.24 g cm−3. In rate zonal sedimentation their apparent mass is less than that of HBV (Sureau et al., 1992).
The HDV genome consists of a single molecule of circular, negative-sense single-stranded RNA of approximately 1.7 kb. With a high degree (ca. 70%) of intramolecular base pairing, it has the potential to fold on itself, forming an unbranched rod-like structure (Wang et al., 1986). Both genomic and antigenomic RNA species contain sequences with ribozyme functions that carry out self-cleavage and possibly self-ligation (Kuo et al., 1988). These properties make the HDV genome unique and distinct from all other animal viruses.
HDV RNA encodes S-HDAg and L-HDAg. The latter protein is formed via an event mediated by the cellular enzyme adenosine deaminase acting on double-stranded RNA (ADAR1) which converts the UAG stop codon of the ORF encoding S-HDAg to UGG, thereby allowing read-through translation giving rise to a L-HDAg that is 19 amino acid residues longer (Polson et al., 1996). Both HDAg forms are multifunctional with domains responsible for (from the N- to C-terminus): (i) dimerization via a coiled-coil structure; (ii) nuclear-localization via a bipartite signal; and (iii) RNA-binding via two arginine-rich motifs. In addition, L-HDAg has a domain that includes a prenylation site required for packaging (Moraleda et al., 2000). The two HDAg forms play distinct roles in replication: S-HDAg is essential for HDV replication, whereas L-HDAg is essential for packaging and in some situations, may inhibit replication (Taylor 2015). HDAg can be phosphorylated at serine residues. The remaining structural proteins of the HDV virion consist of the HDV envelope formed by the surface proteins and glycoproteins encoded by the helper hepadnavirus.
Lipids are present but have not been characterized.
Carbohydrates on the HDV virion are not fully characterized but N-acetylglucosamine is the main carbohydrate component of the envelope proteins of HBV, the natural helper virus for HDV.
The mechanism of HDV entry into human hepatocytes appears similar to that of the helper hepadnavirus. Both viruses require the S and pre-S1 domains of the HBV envelope proteins for virion attachment to and entry into susceptible cells. Cell entry occurs upon binding of the pre-S1 domain to a cellular receptor, sodium taurocholate co-transporting polypeptide (NTCP) (Yan et al., 2012). NTCP is expressed on the basolateral membrane of hepatocytes and confers susceptibility to human cell lines that support HBV replication from transfected DNA but are otherwise refractory to virion entry.
HDV genome replication involves RNA-directed RNA synthesis in the nucleus by host cell RNA polymerase II (Taylor 2015). Transcription is thought to occur by a double-rolling circle mechanism that generates greater-than-genome-length forms of antigenomic and genomic HDV RNA. Both RNA strands contain ribozymes that are responsible for site-specific autocatalytic cleavage and ligation of linear genomes to generate circular genomic and antigenomic monomers (Taylor 1990) (Figure 2.Deltavirus).
Figure 2.Deltavirus. Organization of the genome and antigenome of hepatitis delta virus (M21012). Both RNAs are circular and have the ability to fold into an unbranched rod-like structure via intra-molecular base pairing, with the rod ends at positions 789 and 1630. Each RNA has a ribozyme, with the cleavage sites as indicated. Deamination of a UAG termination codon at the end of the small delta antigen ORF (red) results in the expression of a 19 aa extension (pink) to produce large delta antigen.
The HDV antigenomic strand encodes the hepatitis delta antigen (HDAg) (Wang et al., 1986, Makino et al., 1987). In transfected cells, S-HDAg is produced initially from a linear, approximately 900 nucleotide RNA that is 5′-capped and 3′-polyadenylated. The S-HDAg functions as a transactivator of HDV RNA replication, (Kuo et al., 1989). At a later stage, L-HDAg mRNA is generated as the result of RNA deamination resulting in read-through translation. A similar event occurs during HDV replication in tissue culture, and infected chimpanzees and woodchucks.
As HDV assembly requires the envelope proteins of a helper hepadnavirus, the assembly pathway of HDV likely overlaps with that of HBV. In dually transfected cells, S-HDAg protein is involved in HDV RNA replication at the early stage of infection, whereas L-HDAg is required for the assembly and release of virions. Full size or deleted HDV RNA molecules are incorporated into virus particles, as long as they are capable of folding into rod-like structures and binding to HDAg. In cells undergoing HDV RNA replication, this process is highly specific for genomic RNA, whereas in cells expressing but not replicating HDV RNA, either genome or antigenome RNA can be assembled.
Antibodies to HDAg are diagnostic of current or past infections.
Full replication of HDV requires the presence of a helper hepadnavirus to provide envelope proteins. HDV can, therefore, be considered as a satellite virus. Natural HDV infection is found only in humans infected with HBV in whom HBV acts as a helper virus. However, HDV can be transmitted to chimpanzees if accompanied by HBV, and experimental transmission of HDV to woodchucks (Marmota monax) has also been achieved using woodchuck hepatitis virus as helper virus.
Transmission of HDV to laboratory mice has been reported, leading to a single round of HDV genome replication in hepatocytes but no further replication, presumably due to the absence of helper virus.
Transmission of HDV in humans occurs by similar routes as for HBV, although in many parts of the world, transmission by parenteral contact (e.g., in injecting drug users sharing needles) is more prominent than sexual or vertical routes. Transmission of HDV to an individual with chronic HBV infection (superinfection) typically leads to HDV persistence. On the other hand, simultaneous transmission of both HDV and HBV to a naïve host (co-infection) typically leads to transient infection. HDV is distributed globally; the proportion of HBV carriers who also have chronic HDV infection varies greatly between 0% and 60% in different geographical areas.
Clinical sequelae of acute and chronic HDV infection are variable and cover a similar spectrum to those of HBV alone (Sureau and Negro 2016): acute hepatitis, chronic active hepatitis, cirrhosis, fulminant acute hepatitis, and hepatocellular carcinoma. However, the frequency of severe sequelae and their rates of progression are significantly higher in chronic HDV infection than in chronic HBV infection alone. A subacute, rapidly progressive form of HDV superinfection has been seen in HBV carriers in Venezuela, and other forms of severe acute and chronic often fatal HDV infection, previously recognized as Labrea hepatitis (Dias and Moraes 1973), occur in indigenous populations of Brazil, Venezuela, Colombia, and Peru (Braga et al., 2012).
Delta: A novel antigen in HBV infected tissue, unrelated to previously described HBV antigens, was named delta antigen (δAg) (Rizzetto et al., 1977).
Independent isolates of HDV have up to 40% variation in nucleotide sequence with up to 25 nucleotides variation in length. Comparison of nucleotide sequences have distinguished eight major monophyletic clades or genotypes, HDV1 to HDV8 (Le Gal et al., 2017, Le Gal et al., 2006) (Figure 3.Deltavirus). There is some geographical clustering, with HDV1 found in USA, Europe and China, HDV2 and HDV4 found in Japan and Taiwan, HDV3 found in South America predominantly associated with HBV genotype F, and HDV5, HDV6, HDV7, and HDV8 found in Africa. Natural intergenotype recombinants between HDV1 and HDV2 have been described (Wu et al., 1999).
Figure 3.Deltavirus. Phylogenetic analysis of hepatitis delta virus S-HDAg nucleotide sequences. Hepatitis delta virus nucleotide sequences longer than 1500 nucleotides and differing from each other by >10% were aligned using MUSCLE (Edgar 2004) within the SSE package (Simmonds 2012) and used to produce a neighbour joining phylogenetic tree based on maximum composite likelihood distances in MEGA7 (Kumar et al., 2016). Branches supported in >70% of bootstrap replicates are indicated. Tip symbols are colour coded according to HDV clade. This phylogenetic tree and corresponding sequence alignment are available to download from the Resources page.
Several features of HDV, such as genome structure, RNA-RNA transcription using a host RNA polymerase II, the presence of autocatalytic RNA sites, and RNA-to-RNA rolling circle replication are similar to those of viroids, (Taylor 2015) and some virusoids, helper-dependent viroid-like satellite RNAs (Flores et al., 2012). However, HDV possesses a larger genome than viroids, and apart from a viroid-like RNA region, it has a central conserved region and a region encoding a functional protein. HDV also requires a specific hepadnavirus helper function.
The evolutionary origins of HDV and viroids and their evolutionary relationships are uncertain (Elena et al., 1991, Jenkins et al., 2000). Based on the genome length and structure, mode of replication, protein coding strategy, virion structure and satellite-helper virus relationship, none of the above-mentioned satellite agents warrant inclusion in a family together with HDV.
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