Hepatitis D virus

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Hepatitis D virus
Systematics
Classification : Viruses
Area : unclassified
Phylum : unclassified
Order : unclassified
Family : unclassified
Genre : Delta virus
Type : Hepatitis D virus
Taxonomic characteristics
Genome : (-) ss RNA circular
Baltimore : Group 5
Symmetry : available
Cover : available
Scientific name
Hepatitis delta virus
Short name
HDV
Left

The hepatitis D virus ( hepatitis delta virus , HDV, as a genus also called delta virus or earlier δ agent ) is a virusoid that only occurs naturally in humans, i.e. one of the gene products of another virus ( hepatitis B virus , HBV) dependent virus. It can only form new infectious particles in a cell if this cell is simultaneously infected with HBV and the envelope proteins (HBs antigens) of HBV are produced. The hepatitis D virus causes chronic inflammation of the liver, hepatitis D , which can occur at the same time as fresh hepatitis B ( simultaneous infection) or as an additional infection in chronic hepatitis B ( superinfection ). Its RNA genome, which is unique in the animal world, shows a structural and functional relationship with some viral pathogens in plants. Due to its special genome structure and mode of replication, HDV is considered a molecular relic of chemical evolution and supports the assumptions of the RNA world hypothesis . The previous assignment to the Riboviria division was withdrawn by the International Committee on Taxonomy of Viruses (ICTV) in March 2020.

discovery

The Turin-based gastroenterologist Mario Rizzetto and his group reported in 1977 on the detection of a previously unknown protein in liver biopsies of some patients who were chronically infected with the hepatitis B virus (HBV) during a major outbreak of HBV in the Mediterranean region in the mid-1970s. had been infected. Rizzetto had previously dealt with the detection of HBV proteins by immunofluorescence in the nuclei of infected liver cells. He initially considered the new protein to be a previously unrecognized HBV antigen , which he was also able to detect in the cell nuclei of infected liver cells. Since it was closely associated with the already known core antigen of HBV (HBc antigen), he named the new protein "Delta antigen". Patients with the delta antigen also developed specific antibodies against this protein.

The delta antigen could indeed be detected in HBV-infected cells, but not in purified HBV virions . It was therefore not a structural protein of HBV and was only found during virus replication. In collaboration with Robert H. Purcell and John L. Gerin , chimpanzees were infected with patient samples containing delta antigen. Experiments with chimpanzees in research into HBV infections had been conducted since the early 1970s. In the blood serum of an infected animal, Purcell, Gerin and Rizzetto were finally able to detect virus particles that contained delta antigen, but were significantly smaller than HBV virions (35 to 37 nm compared to about 50 nm). The particles were associated with an RNA molecule that differed from the viral mRNA molecules of HBV and was very small for all RNA genomes known to date in animal viruses ( molecular mass only 5 × 10 5 ). This provided proof that it was a newly discovered virus and that the delta antigen was a component of this new virus.

On the basis of purified Delta antigen, a radioimmunoassay and an ELISA test were developed in 1981 that recognized specific anti-HDV antibodies in the blood serum of patients. The antibodies have been found in a large number of patients infected with HBV worldwide; Evidence was found particularly frequently in HBV patients from the Mediterranean region, haemophiles and addicts of intravenous drugs. The anti-HDV antibodies were not found in blood samples from anti-HBc-negative patients, i.e. people who were never or are never infected with HBV. This led to the conclusion that HDV is only associated with HBV and, similar to HBV , it is transmitted parenterally through blood.

The RNA of HDV was characterized more precisely by A. Kos at the Primate Center in Rijswijk (Netherlands) in 1986 and recognized as a single-stranded, circularly closed ring. The first short sequencing of the RNA showed the high similarity of HDV to viroids , the infectious RNA molecules found in plants. The hydrodynamic diameter of the HDV virions was determined in 1986 by Ferruccio Bonino and Wolfram H. Gerlich by means of gel filtration to be 36 nm; they also demonstrated for the first time the existence of two differently sized forms of the delta antigen and that the virus envelope of HDV consists almost exclusively of the smallest of the three HBV envelope proteins of HBV (sHBs antigen).

Distribution and host range

HDV is widespread worldwide, with a particularly high prevalence in southern Italy and the entire Mediterranean region. Regionally high prevalences are also found in Romania , Mongolia and some countries in Central Africa and South America ( Venezuela , Colombia , eastern Brazil ). The prevalence of HDV is largely the same as the frequency of chronic HBV infections. In contrast to this, the HDV prevalence in China is comparatively low at around 9% of chronically HBV infected people. In developed countries, the prevalence of HDV in the general population is low, but it is increased in groups of people at high risk of parenteral transmission, particularly those with IV drug abuse. In HDV, three genotypes can be distinguished based on the genome sequence , with genotype 1 being detected worldwide, genotype 2 being dominant in Asia (mainly Taiwan and Japan ) and genotype 3 originally only being detected in South America.

A natural host other than humans has not yet been described for HDV; liver cells are the only place of virus replication. Under experimental conditions, managed the infection of chimpanzees in the presence of HBV and woodchucks ( woodchucks ), if these bear the HBV-like Woodchuck hepatitis virus (WHV), genus Orthohepadnavirus were infected. In the latter case, HDV virions arose in whose viral envelope the WHV-S antigen was present. Stably HDV-infected cell cultures could not be established so far. After the introduction ( transfection ) of experimentally produced, complementary HDV-RNA (HDV- cDNA ) into cell cultures, replicating HDV-RNA and delta antigen can be detected. Since this replication can be carried out in very different cell lines , it can be assumed that the natural strict tropism for liver cells is due to specific receptors on the cell surface. As long as HBs antigen is not also synthesized in the transfected cells at the same time, however, the HDV capsids are not packaged and thus infectious HDV virions are not produced.

Virus structure

Virus genome

The genome of HDV consists of a 1,670 to 1,683 nucleotide single-stranded RNA with negative polarity (-ssRNA). The GC content is comparatively high at around 60%. HDV is the only virus pathogenic to humans whose genomic RNA is closed (circular) in a ring. This is only visible under denaturing conditions in the electron microscope . Under non-denaturing, physiological conditions, intramolecular base pairs are formed within the RNA strand in a range of around 70% and the RNA then appears as an unbranched, rod-shaped strand. The HDV genome only codes for a single protein, the HDV antigen, whose open reading frame (ORF) lies on the complementary, positive-stranded RNA. Both RNA strands (genomic -ssRNA and antigenomic + ssRNA) produced during RNA replication have ribozyme activity.

morphology

The 36 nm in diameter, enveloped virions have an 18 nm large, spherical nucleocapsid inside , which is formed from the genomic RNA and the surrounding HDV antigen. The density of the virions in density gradient centrifugation with cesium chloride 1.25 g / ml and thus the density of other enveloped viruses is comparable. HDV has compared to other enveloped viruses very high environmental stability and may not even at temperatures up to 60 ° C for 30 hours inactivates be.

Classification and importance in virus evolution

A classification of the hepatitis D virus within the virus taxonomy encounters the difficulty that it has no similarity to other viruses with regard to the genome sequence and the replication mechanism. Without being assigned to a virus family, it is currently the only species in the genus Deltavirus . There is a relationship at the level of the genome sequence of a viroid-like section of HDV only with a few satellite viruses of plant viruses , which also occur as single-stranded, circular RNA. In contrast to HDV, however, these do not have a shell. These closely related viroid satellites include the Velvet Tobacco Mottle Virus (vVTMoV), the Subterranean Clover Mottle Virus (vSCMoV), the Lucerne Transient Streak Virus (vLTSV), and the Solanum nodiflorum Mottle virus (vSNMV). A common, evolutionary predecessor of HDV and the plant viroids can thus be assumed.

The aforementioned viroid satellites and HDV are viewed as archaic relics from the earliest stages of cell-free molecular evolution due to their special RNA genome, which has both genotypic and phenotypic properties. As possible “living fossils” , their RNA can multiply without proteins (RNA polymerases) or DNA intermediates, since the RNA genome has the ability to autonomously reproduce, to enzymatically split itself (autolysis through ribozyme activity) and to stick together owns its own RNA fragments (RNA ligation). These viral systems are at the transition from chemical to biological evolution and represent properties that can be derived from the hypothesis of the hypercycle and the emergence of evolutionary quasi-species . These archaic viral RNA genomes may reflect an all-RNA precursor in the origin of life, which is assumed in the so-called RNA world hypothesis .

Reporting requirement

In Germany, all direct or indirect evidence of the hepatitis D virus must be reported by name in accordance with Section 7 of the Infection Protection Act .

literature

  • Michael MC Lai: Hepatitis Delta Virus. In: Allan Granoff, Robert G. Webster: Encyclopedia of Virology. San Diego 1999, (Volume 1) pp. 664-669, ISBN 0-12-227030-4 .
  • David M. Knipe, Peter M. Howley (Eds.): Fields' Virology. 5th edition, 2 volumes. Philadelphia 2007, ISBN 0-7817-6060-7 .
  • A. Smedile and M. Rizzetto: HDV: thirty years later. Dig. Liver Dis. (2011) 43 Suppl 1, pp. 15-18, PMID 21195366 .

Individual evidence

  1. a b c d e ICTV: ICTV Taxonomy history: Hepatitis delta virus , EC 51, Berlin, Germany, July 2019; Email ratification March 2020 (MSL # 35)
  2. M. Rizzetto, MG Canese et al. : Immunofluorescence detection of new antigen-antibody system (delta / anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut (1977) 18 (12), pp. 997-1003, PMID 75123 , PMC 1411847 (free full text)
  3. MG Canese, M. Rizzetto et al. : An ultrastructural and immunohistochemical study on the delta antigen associated with the hepatitis B virus. J. Pathol. (1979) 128 (4), pp. 169-175, PMID 392063
  4. Rizzetto M, Hoyer B, Canese MG, Shih JW, Purcell RH, Gerin JL: δ Agent: association of δ antigen with hepatitis B surface antigen and RNA in serum of δ-infected chimpanzees . Proc Natl Acad Sci US A. (1980) 77 (10), pp. 6124-6128, PMID 6934539 , PMC 350226 (free full text).
  5. M. Rizzetto, MGJ Canese et al. : Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. Infect. Dis. (1980) 141 (5), pp. 590-602, PMID 6989929 .
  6. O. Crivelli, M. Rizzetto et al. : Enzyme-linked immunosorbent assay for detection of antibody to the hepatitis B surface antigen-associated delta antigen. J. Clin. Microbiol. (1981) 14 (2), pp. 173-177, PMID 7024305 , PMC 271929 (free full text).
  7. A. Kos, R. Dijkema et al. : The hepatitis delta (delta) virus possesses a circular RNA. Nature (1986) 323 (6088), pp. 558-560, PMID 2429192
  8. F. Bonino, KH Heermann, M. Rizzetto and WH Gerlich: Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J. Virol. (1986) 58 (3), pp. 945-950, PMID 3701932 , PMC 253003 (free full text).
  9. SF Elena, J. Dopazo et al .: Phylogeny of viroids, viroidlike satellite RNAs, and the viroidlike domain of hepatitis delta virus RNA. Proc. Natl. Acad. Sci. US A. (1991) 88 (13), pp. 5631-5634 PMID 1712103 , PMC 51931 (free full text).
  10. TO Diener : Circular RNAs: relics of precellular evolution? Proc. Natl. Acad. Sci. US A. (1989) 86 (23), pp. 9370-9374, PMID 2480600 , PMC 298497 (free full text).

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