in 1977 a young Italian physician, Rizzetto, detected a novel antigen, which he called 5 (delta), in the nuclei of hepatocytes from particularly severe cases of hepatitis B Delta antigen was also found inside 36 nm viruslike particles, the "delta agent," the outer coat of which was serologically indistinguishable from HBsAg. It transpired that the 8 agent, now known as hepatitis D virus (HDV), is a defective satellite virus, found only in association with its helper virus, HBV. The tiny RNA genome of HDV, smaller than that of any known animal virus, encodes its own nucleoprotein (the delta antigen), but the outer capsid of the HDV virion is composed of HBsAg, encoded by the genome of HBV coinfecting the same cell.
Currently classified as the sole member of a new free-standing genus, Deltavirus, HDV is absolutely unique among human viruses, and indeed is without precedent among mammalian viruses. Some regard it as a subviral agent falling outside the definition of a virus. It displays features characteristic of several different classes of plant pathogens known as viroids, virusoids, satellite RNAs, and satellite viruses, all of which have RNA genomes resembling that of HDV in certain respects, but some of which encode no coat protein or no proteins at all. The HDV genome, like that of several of these subviral plant pathogens, is a covalently closed circle of single-stranded RNA with self-cleaving (ribozyme) and self-ligating activity. Although HDV is currently the only known mammalian example of this strange class of agents, it is reasonable to suppose that other comparable infectious agents of humans await discovery.
The HDV virion is roughly spherical and heterogeneous in size (30-40 nm with a mean of 36-38 nm). The coat is composed of HBsAg, mainly lacking the pre-S regions. The genome is a covalently closed circle of minus sense RNA of only 1.7 kb, with extensive base pairing creating a secondary structure enabling it to fold into an unbranched rodlike structure. There is no sequence similarity (homology) with either HBV DNA or cellular DNA. Currently, the only known gene product is HDAg, which is encoded by the largest ORF on the antigenome. HDAg has at least three functional domains: (1) an RNA-binding domain, which no doubt accounts for its intimate association with the viral genome, (2) a nuclear localization signal, which directs the infecting genome and newly synthesized HDAg to the site of viral transcription and replication, and (3) a leucine zipper, which is assumed to promote interaction between HDAg and HBsAg in assembly of the virion (Table 22-4)
Pioperties of Hepatitis D Virus
Satellite virus requiring hepatitis 1} virus as helper, by HDV/HIJV reinfection or by superinfection of f IBV carrier
Spherical virion, 36-38 nm, HBsAg coat, HDAg nuclcoprotein
Circular minus sense ssRNA genome, 1 7 kb
Transcription and genome leplication occur in nucleus using host RNA polymerase II
RNA replication by rolling circle mechanism, ribo/.yme self-cleavage of multimeric nascent strand, then self-ligation to circularize
RNA editing allows read through of stop codon to yield two versions of HDAg which regulate replication, morphogenesis, and release
Although HDV can be grown in primary cultures of hepatocytes in the presence of its helper virus HBV, this is too cumbersome a system to produce definitive biochemical data on the details of viral replication. However, a number of clear-cut and surprising findings have come from transfection experiments using either (1) genetically cloned DNA copies of the HDV RNA genome or (2) genomic RNA itself, delivered in liposomes to cells that have been engineered to express HDAg. Replication of the HDV genome itself requires neither hepatocytes, human cells, nor HBV; a wide range of mammalian cells will support HDV RNA replication in the absence of HBV, but the latter is necessary for the production of HDV virions.
Following entry and uncoating, the genome with associated HDAg is transported to the nucleus where it utilizes the host RNA polymerase II to transcribe complementary RNA of two distinct forms: (1) full-length circular plus sense RNA, the "antigenome," which serves as the intermediate in replication of the genome, and (2) a shorter polyadenylated linear transcript that is exported to the cytoplasm and serves as mRNA for translation into HDAg. Replication of the genome occurs in the nucleus by what is known in plant viroids as the double rolling circle mechanism; the template rolls as the anti-genome is synthesized, to produce excessively long plus strand linear copies (Fig. 22-7). This multimeric transcript then cleaves itself to yield a unit-length antigenome, one specific nucleotide sequence serving as the substrate (cleavage site) and another as a magnesium-dependent enzyme. A ligase activity then joins the ends of the linear transcript to yield the monomeric closed circular plus sense RNA antigenome. A similar sequence of events then generates new copies of the genome, using the antigenome as a template.
During RNA replication ol HDV an extraordinary example of RNA editing is observed; a specific mutation (UAG —»■ UGG) occurs in the lermination codon at the end of the ORF for the truncated (small) form of HDAg (P24), enabling the host RNA polymerase II to read through it to yield the mRNA encoding the large form of HDAg (P27). P24 is required for HDV RNA replication whereas P27 inhibits it, hence the switch from production of P24 to P27 suppresses further genome replication and promotes its packaging. Assembly of the genome-HDAg complex with HBsAg in the cytoplasm then produces the complete virion for release from the cell.
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