Hepatitis D

Hepatitis D
Classification and external resources
Specialty infectious disease
ICD-10 B17.0, B18.0
ICD-9-CM 070.31
DiseasesDB 5792
MeSH D003699

Hepatitis D (hepatitis delta) is a disease caused by the hepatitis D virus (HDV), a small spherical enveloped RNA virus. This is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a subviral satellite because it can propagate only in the presence of the hepatitis B virus (HBV).[1] Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).

Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections.[2] In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.

Virology

Hepatitis D
Schematic representation of the hepatitis delta virus virion.
Virus classification
Group: Group V ((-)ssRNA)
Order: Unassigned
Family: Unassigned
Genus: Deltavirus
Species: Hepatitis delta virus

Structure and genome

Hepatitis delta virus delta antigen

oligomerization domain of hepatitis delta antigen
Identifiers
Symbol HDV_ag
Pfam PF01517
InterPro IPR002506
SCOP 1a92
SUPERFAMILY 1a92

The HDV is a small, spherical virus with a 36 nm diameter. It has an outer coat containing three kinds of HBV envelope protein - large, medium, and small hepatitis B surface antigens - and host lipids surrounding an inner nucleocapsid. The nucleocapsid contains single-stranded, circular RNA of 1679 nucleotides and about 200 molecules of hepatitis D antigen (HDAg) for each genome. The central region of HDAg has been shown to bind RNA.[3] Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg.[4] The hepatitis D circular genome is unique to animal viruses because of its high GC nucleotide content. The HDV genome exists as an enveloped, negative sense, single-stranded, closed circular RNA. Its nucleotide sequence is 70% self-complementary, allowing the genome to form a partially double-stranded, rod-like RNA structure.[5] With a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals. It has been proposed that HDV may have originated from a class of plant pathogens called viroids, which are much smaller than viruses.[6][7]

Life cycle

Like Hepatitis B, HDV gains entry into liver cells via the NTCP[8] bile transporter. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg.[9] Mapping by mutagenesis of this domain has shown that amino acid residues 9–15 make up the receptor binding site.[10] After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg[11] Since the nucleocapsid does not contain an RNA polymerase to replicate the virus’ genome, the virus makes use of the cellular RNA polymerases. Initially just RNA pol II,[12][13] now RNA polymerases I and III have also been shown to be involved in HDV replication[14] Normally RNA polymerase II utilizes DNA as a template and produces mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known animal pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.

The RNA polymerases treat the RNA genome as double stranded DNA due to the folded rod-like structure it is in. Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in the nucleolus, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II.[15] HDV RNA is synthesized first as linear RNA that contains many copies of the genome. The genomic and antigenomic RNA contain a sequence of 85 nucleotides, the Hepatitis delta virus ribozyme, that acts as a ribozyme, which self-cleaves the linear RNA into monomers. These monomers are then ligated to form circular RNA.[16][17]

There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity.

Delta antigens

A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV is known to produce one protein, namely HDAg. It comes in two forms; a 27kDa large-HDAg, and a small-HDAg of 24kDa. The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg.[18] Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase-1 changes the stop codon to UCG, allowing the large-HDAg to be produced.[18][19] Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles.[20][21][22] Thus RNA editing by the cellular enzymes is critical to the virus’ life cycle because it regulates the balance between viral replication and virion assembly.

Transmission

The routes of transmission of hepatitis D are similar to those for hepatitis B. Infection is largely restricted to persons at high risk of hepatitis B infection, particularly injecting drug users and persons receiving clotting factor concentrates. Worldwide more than 15 million people are co-infected. HDV is rare in most developed countries, and is mostly associated with intravenous drug use. However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America.[23] In all, about 20 million people may be infected with HDV.[24]

Treatment and prevention

The vaccine for hepatitis B protects against hepatitis D virus because of the latter's dependence on the presence of hepatitis B virus for it to replicate.[25][26]

Latest evidence suggests that Pegylated interferon alpha is effective in reducing the viral load and the effect of the disease during the time the drug is given, but the benefit generally stops if the drug is discontinued.[27] The efficiency of the pegylated interferon treatment does not usually exceed ~20%.[28]

The drug myrcludex B, which inhibits virus entry into hepatocytes, is in clinical trials as of October 2015.[29]

History

Hepatitis D virus was first reported in the mid-1977 as a nuclear antigen in patients infected with HBV who had severe liver disease.[30] This nuclear antigen was then thought to be a hepatitis B antigen and was called the delta antigen. Subsequent experiments in chimpanzees showed that the hepatitis delta antigen (HDAg) was a structural part of a pathogen that required HBV infection to replicate.[31] The entire genome was cloned and sequenced in 1986. It was subsequently placed in its own genus: Deltavirus.[32][33]

Evolution

Three genotypes (I–III) were originally described. Genotype I has been isolated in Europe, North America, Africa and some Asia. Genotype II has been found in Japan, Taiwan, and Yakutia (Russia). Genotype III has been found exclusively in South America (Peru, Colombia, and Venezuela). Some genomes from Taiwan and the Okinawa islands have been difficult to type but have been placed in genotype 2. However it is now known that there are at least 8 genotypes of this virus (HDV-1 to HDV-8).[34] Phylogenetic studies suggest an African origin for this pathogen.[35]

An analysis of 36 strains of genotype 3 estimated that the most recent common ancestor of these strains originated around 1930.[36] This genotype spread exponentially from early 1950s to the 1970s in South America. The substitution rate was estimated to be 1.07×10−3 substitutions per site per year.

Genotype 8 has also been isolated from South America. This genotype is usually only found in Africa and may have been imported into South America during the slave trade.[37]

Genotypes, with the exception of type 1, appear to be restricted to certain geographical areas: HDV-2 (previously HDV-IIa) is found in Japan, Taiwan and Yakoutia, Russia; HDV-4 (previously HDV-IIb) in Japan and Taiwan; HDV-3 in the Amazonian region; HDV-5, HDV-6, HDV-7 and HDV-8 in Africa.[38]

See also

References

  1. ↑ Makino S, Chang MF, Shieh CK, et al. (1987). "Molecular cloning and sequencing of a human hepatitis delta (delta) virus RNA". Nature. 329 (6137): 343–6. doi:10.1038/329343a0. PMID 3627276.
  2. ↑ Fattovich G, Giustina G, Christensen E, et al. (March 2000). "Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B". Gut. 46 (3): 420–6. doi:10.1136/gut.46.3.420. PMC 1727859Freely accessible. PMID 10673308.
  3. ↑ Poisson F, Roingeard P, Baillou A, Dubois F, Bonelli F, Calogero RA, Goudeau A; Roingeard; Baillou; Dubois; Bonelli; Calogero; Goudeau (November 1993). "Characterization of RNA-binding domains of hepatitis delta antigen". J. Gen. Virol. 74 (Pt 11): 2473–8. doi:10.1099/0022-1317-74-11-2473. PMID 8245865.
  4. ↑ Zuccola HJ, Rozzelle JE, Lemon SM, Erickson BW, Hogle JM; Rozzelle; Lemon; Erickson; Hogle (July 1998). "Structural basis of the oligomerization of hepatitis delta antigen". Structure. 6 (7): 821–30. doi:10.1016/S0969-2126(98)00084-7. PMID 9687364.
  5. ↑ Saldanha JA, Thomas HC, Monjardino JP; Thomas; Monjardino (July 1990). "Cloning and sequencing of RNA of hepatitis delta virus isolated from human serum". J. Gen. Virol. 71 (7): 1603–6. doi:10.1099/0022-1317-71-7-1603. PMID 2374010.
  6. ↑ Elena SF, Dopazo J, Flores R, Diener TO, Moya A; Dopazo; Flores; Diener; Moya (July 1991). "Phylogeny of viroids, viroidlike satellite RNAs, and the viroidlike domain of hepatitis delta virus RNA". Proc. Natl. Acad. Sci. U.S.A. 88 (13): 5631–4. doi:10.1073/pnas.88.13.5631. PMC 51931Freely accessible. PMID 1712103.
  7. ↑ Sureau, C (2006). "The role of the HBV envelope proteins in the HDV replication cycle". Current topics in microbiology and immunology. Current Topics in Microbiology and Immunology. 307: 113–31. doi:10.1007/3-540-29802-9_6. ISBN 978-3-540-29801-4. PMID 16903223.
  8. ↑ Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W; Zhong; Xu; He; Jing; Gao; Huang; Qi; Peng; Wang; Fu; Song; Chen; Gao; Ren; Sun; Cai; Feng; Sui; Li (2012). "Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus". ELife. 1: e00049. doi:10.7554/eLife.00049. PMC 3485615Freely accessible. PMID 23150796.
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  11. ↑ Xia, YP; Yeh, CT, Ou, JH, Lai, MM (February 1992). "Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a protein complex". Journal of Virology. 66 (2): 914–21. PMC 240792Freely accessible. PMID 1731113.
  12. ↑ Lehmann E, Brueckner F, Cramer P; Brueckner; Cramer (November 2007). "Molecular basis of RNA-dependent RNA polymerase II activity". Nature. 450 (7168): 445–9. doi:10.1038/nature06290. PMID 18004386.
  13. ↑ Filipovska J, Konarska MM; Konarska (January 2000). "Specific HDV RNA-templated transcription by pol II in vitro". RNA. 6 (1): 41–54. doi:10.1017/S1355838200991167. PMC 1369892Freely accessible. PMID 10668797.
  14. ↑ Greco-Stewart, VS; Schissel, E; Pelchat, M (2009-03-30). "The hepatitis delta virus RNA genome interacts with the human RNA polymerases I and III". Virology. 386 (1): 12–5. doi:10.1016/j.virol.2009.02.007. PMID 19246067.
  15. ↑ Li, YJ; Macnaughton, T; Gao, L; Lai, MM (July 2006). "RNA-Templated Replication of Hepatitis Delta Virus: Genomic and Antigenomic RNAs Associate with Different Nuclear Bodies". Journal of Virology. 80 (13): 6478–86. doi:10.1128/JVI.02650-05. PMC 1488965Freely accessible. PMID 16775335.
  16. ↑ Branch, AD; Benenfeld, BJ, Baroudy, BM, Wells, FV, Gerin, JL, Robertson, HD (1989-02-03). "An ultraviolet-sensitive RNA structural element in a viroid-like domain of the hepatitis delta virus". Science. 243 (4891): 649–52. doi:10.1126/science.2492676. PMID 2492676.
  17. ↑ Wu, HN; Lin, YJ, Lin, FP, Makino, S, Chang, MF, Lai, MM (March 1989). "Human hepatitis delta virus RNA subfragments contain an autocleavage activity". Proceedings of the National Academy of Sciences of the United States of America. 86 (6): 1831–5. doi:10.1073/pnas.86.6.1831. PMC 286798Freely accessible. PMID 2648383.
  18. 1 2 Weiner, AJ; Choo, QL, Wang, KS, Govindarajan, S, Redeker, AG, Gerin, JL, Houghton, M (February 1988). "A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta". Journal of Virology. 62 (2): 594–9. PMC 250573Freely accessible. PMID 2447291.
  19. ↑ Jayan, GC; Casey, JL (December 2002). "Inhibition of Hepatitis Delta Virus RNA Editing by Short Inhibitory RNA-Mediated Knockdown of ADAR1 but Not ADAR2 Expression". Journal of Virology. 76 (23): 12399–404. doi:10.1128/JVI.76.23.12399-12404.2002. PMC 136899Freely accessible. PMID 12414985.
  20. ↑ Sato S, Cornillez-Ty C, Lazinski DW; Cornillez-Ty; Lazinski (August 2004). "By Inhibiting Replication, the Large Hepatitis Delta Antigen Can Indirectly Regulate Amber/W Editing and Its Own Expression". J. Virol. 78 (15): 8120–34. doi:10.1128/JVI.78.15.8120-8134.2004. PMC 446097Freely accessible. PMID 15254184.
  21. ↑ Taylor, JM (2006). "Structure and replication of hepatitis delta virus RNA". Current topics in microbiology and immunology. Current Topics in Microbiology and Immunology. 307: 1–23. doi:10.1007/3-540-29802-9_1. ISBN 978-3-540-29801-4. PMID 16903218.
  22. ↑ Chang, MF; Chen, CJ, Chang, SC (February 1994). "Mutational analysis of delta antigen: effect on assembly and replication of hepatitis delta virus". Journal of Virology. 68 (2): 646–53. PMC 236498Freely accessible. PMID 8289368.
  23. ↑ Radjef N, Gordien E, Ivaniushina V, et al. (March 2004). "Molecular Phylogenetic Analyses Indicate a Wide and Ancient Radiation of African Hepatitis Delta Virus, Suggesting a Deltavirus Genus of at Least Seven Major Clades". J. Virol. 78 (5): 2537–44. doi:10.1128/JVI.78.5.2537-2544.2004. PMC 369207Freely accessible. PMID 14963156. |first10= missing |last10= in Authors list (help); |first11= missing |last11= in Authors list (help)
  24. ↑ Taylor JM (January 2006). "Hepatitis delta virus". Virology. 344 (1): 71–6. doi:10.1016/j.virol.2005.09.033. PMID 16364738.
  25. ↑ U.S. National Library of Medicine "Delta Agent (hepatitis D)"
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  27. ↑ Abbas, Z.; Khan, MA.; Salih, M.; Jafri, W. (2011). Abbas, Zaigham, ed. "Interferon alpha for chronic hepatitis D". Cochrane Database Syst Rev (12): CD006002. doi:10.1002/14651858.CD006002.pub2. PMID 22161394.
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  29. ↑ Spreitzer, H (14 September 2015). "Neue Wirkstoffe – Myrcludex B". Österreichische Apothekerzeitung (in German) (19/2015): 12.
  30. ↑ Rizzetto M; Canese MG; Arico S; Criello O; Trepo C; Bonino F; Verme G (1977). "Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers". Gut. 18 (12): 997–1003. doi:10.1136/gut.18.12.997. PMC 1411847Freely accessible. PMID 75123.
  31. ↑ Rizzetto, M; Canese, MG, Purcell, RH, London, WT, Sly, LD, Gerin, JL (Nov–Dec 1981). "Experimental HBV and delta infections of chimpanzees: occurrence and significance of intrahepatic immune complexes of HBcAg and delta antigen". Hepatology (Baltimore, Md.). 1 (6): 567–74. doi:10.1002/hep.1840010602. PMID 7030907.
  32. ↑ Wang, KS; Choo, QL, Weiner, AJ, Ou, JH, Najarian, RC, Thayer, RM, Mullenbach, GT, Denniston, KJ, Gerin, JL, Houghton, M (Oct 9–15, 1986). "Structure, sequence and expression of the hepatitis delta (delta) viral genome". Nature. 323 (6088): 508–14. doi:10.1038/323508a0. PMID 3762705.
  33. ↑ Fauquet, CM; Mayo MA; Maniloff J; Desselberger U; Ball LA (2005). "Deltavirus". Eight Report of the International Committee on Taxonomy of Viruses. London: 735–8.
  34. ↑ Celik I, Karataylı E, Cevik E, et al. (December 2011). "Complete genome sequences and phylogenetic analysis of hepatitis delta viruses isolated from nine Turkish patients". Arch. Virol. 156 (12): 2215–20. doi:10.1007/s00705-011-1120-y. PMID 21984217.
  35. ↑ Radjef, N.; Gordien, E.; Ivaniushina, V.; Gault, E.; Anaïs, P.; Drugan, T.; Trinchet, J. C; Roulot, D.; Tamby, M.; Milinkovitch, M. C.; Dény, P. (2004). "Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades". J Virol. 78 (5): 2537–44. doi:10.1128/JVI.78.5.2537-2544.2004. PMC 369207Freely accessible. PMID 14963156.
  36. ↑ Alvarado-Mora, M. V.; Romano, C. M.; Gomes-Gouvêa, M. S.; Gutierrez, M. F.; Carrilho, F. J.; Pinho, J. R. (2011). "Dynamics of hepatitis D (delta) virus genotype 3 in the Amazon region of South America". Infect Genet Evol. Elsevier. 11 (6): 1462–8. doi:10.1016/j.meegid.2011.05.020. PMID 21645647.
  37. ↑ Barros, L. M.; Gomes-Gouvêa, M. S.; Pinho, J. R.; Alvarado-Mora, M. V.; Dos Santos, A.; Mendes-Corrêa, M. C.; Caldas, A. J.; Sousa, M. T.; Santos, M. D.; Ferreira, A. S. (2011). "Hepatitis Delta virus genotype 8 infection in Northeast Brazil: inheritance from African slaves?". Virus Res. 160 (1–2): 333–9. doi:10.1016/j.virusres.2011.07.006. PMID 21798297.
  38. ↑ Le Gal, F.; Gault, E.; Ripault, M. P.; Serpaggi, J.; Trinchet, J. C.; Gordien, E.; Dény, P. (2006). "Eighth Major Clade for Hepatitis Delta Virus". Emerg Infect Dis. 12 (9): 1447–50. doi:10.3201/eid1209.060112. PMC 3294742Freely accessible. PMID 17073101.

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