Hepatitis D Virus

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This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Hepatitis D.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Overview

Hepatitis D infection is caused by the hepatitis D virus.

Taxonomy

Viruses; Deltavirus; Hepatitis delta virus

Biology

Electron micrograph revealing the presence of hepatitis-B virus HBV "Dane particles", or virions. Courtesy: World Health Organization[1]

The hepatitis D virus belongs to the genus Deltavirus. Its genome is a single, negative stranded, circular RNA molecule nearly 1.7 kb in length containing about 60% C+G. A high degree of intramolecular complementarity allows about 70% of the nucleotides to be basepaired to each other to form an unbranched, double-stranded, stable, rod-shaped structure.[2][3] Because the viral genome is double-stranded, the virus is relatively stable, being able to survive dry heat at 60°C for 30h. The genome of HDV is unrelated to the genomes of hepadnaviruses, of which hepatitis B virus (HBV) is a member.[4] HDV is a replication defective, helper (HBV) dependent ssRNA virus that requires the surface antigen of HBV (HBsAg) for the "encapsidation" of its own genome. The envelope proteins on the outer surface of HDV are entirely provided by HBV.[5][6]

The outer envelope of HDV particles contains lipids and the three forms (S, M, and L) of HBV surface antigen (HBsAg), but predominantly the major form of HBsAg with very few middle (pre S1) and large (pre S2) proteins. The internal nucleocapsid structure of HDV is composed of the viral single stranded RNA genome and about 60 copies of delta antigen, the only HDV-encoded protein.[6]

HDV does not infect established tissue culture cell lines. Complete viral replication cycles in vitro are limited to primary hepatocytes that are coinfected with a hepadnavirus or cotransfected with hepadnavirus cDNA.[6][2]

Life Cycle

To replicate efficiently, a virus requires the cooperation of the host cell at all stages of the viral replication cycle. These stages include:[6]

  1. Atthment
  2. Penetration
  3. Uncoating
  4. Provision of appropriate metabolic conditions for the synthesis of viral macromolecules
  5. Final assembly of viral subunits
  6. Release of new virions

Hepatitis D virus requires the presence of an helper hepadnavirus to provide the protein components for its own envelope. How HDV enters hepatocytes is still unknown, however, it may involve the interaction between HBsAg-L and the HBV cellular receptor. This assumption is due to the similarities between the outer coats of these two viruses.[7] After entering the host cell, the virus loses its coat.[7] The incoming HDV RNA is then transported into the nucleus, probably by the small form of viral delta antigen, HDAg-S. Binding of HDAg to RNA also protects the HDV RNAs from cellular degradation.[6]

HDV RNA replication is carried out by cellular RNA polymerase II, without a DNA intermediate or help from HBV. During the replication of the HDV genome three forms of RNA are produced:

  • Circular genomic RNA
  • Circular complementary antigenomic RNA
  • Linear polyadenylated antigenomic RNA - mRNA containing the open reading frame for the HDAg.

Synthesis of antigenomic RNA occurs in the nucleus, mediated by RNA polymerase I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Polymerase II.[8] The translation of the HDV mRNA yields:[6][9][2][10]

  • Small (p24) form of HDAg (HDAg-S) - after translated in the cytoplasm, returns to the nucleus to support transcription
  • Large (p27) form of HDAg (HDAg-L) - inhibitor of RNA synthesis and initiator of virion assembly with HBsAg

The HDV particle is composed by:

These elements are only assembled in the presence of the hepatitis B virus, which works as an helper virus. HBsAg and HDAg-L are necessary and sufficient for viral assembly. HDV RNA or HDAg-S, despite present, are not required for this phase. The primary initiation event for HDV assembly is the interaction of HDAg-L with HBsAg. HDAg is localized in the nuclei while HBsAg is present in the cytoplasm of the infected cells. In the nucleus, complexes of small and large HDAg, and new fragments of RNA are formed. These are then transferred to the Golgi membranes, where they will be conjugated with hepatitis B virus envelope proteins, thereby forming the final virion.[7][6][11][12]

Genotypes

The RNA sequence of HDV has great variability. Genotyping techniques have shown the existence of more than 8 different genotypes of HDV.[7]

Different HDV genotypes have been associated with different courses of natural history. Different studies have shown that:[7]

  • Patients with genotype 1 have worst outcomes and lower remission rates than those with HDV genotype 2
  • Genotype 1 commonly leads to a wide range of manifestations of the disease, making it hard to establish a relationship between natural history and genotype
  • Genotype 3 is associated with outbreaks in South America of florid hepatitis, leading to liver failure and death
  • Mild liver disease is often associated with HDV genotype 4
  • In Japan there is a variant of the HDV genotype 4 prone to the development of cirrhosis

Although the genotype of the underlying HBV may also influence the progression of the disease, the effects are difficult to study due to low levels of HBV DNA for genotyping.[7]

Tropism

Hepatitis D shows tropism for hepatocytes.

Natural Reservoir

Humans are the only known natural reservoir of hepatitis D virus. However, when in the presence of hepatitis B virus, or woodchuck hepatitis virus, HDV can be experimentally transmitted to chimpanzees and woodchucks, respectively.[6][2][3][13]

References

  1. "http://www.who.int/en/". External link in |title= (help)
  2. 2.0 2.1 2.2 2.3 Lai MM (1995). "The molecular biology of hepatitis delta virus". Annu Rev Biochem. 64: 259–86. doi:10.1146/annurev.bi.64.070195.001355. PMID 7574482.
  3. 3.0 3.1 Monjardino JP, Saldanha JA (1990). "Delta hepatitis. The disease and the virus". Br Med Bull. 46 (2): 399–407. PMID 2198992.
  4. Nakamura A, Osonoi T, Terauchi Y (2010). "Relationship between urinary sodium excretion and pioglitazone-induced edema". J Diabetes Investig. 1 (5): 208–11. doi:10.1111/j.2040-1124.2010.00046.x. PMC 4020723. PMID 24843434.
  5. Makino S, Chang MF, Shieh CK, Kamahora T, Vannier DM, Govindarajan S; 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.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Hepatitis D" (PDF).
  7. 7.0 7.1 7.2 7.3 7.4 7.5 Hughes SA, Wedemeyer H, Harrison PM (2011). "Hepatitis delta virus". Lancet. 378 (9785): 73–85. doi:10.1016/S0140-6736(10)61931-9. PMID 21511329.
  8. Li, YJ (2006 Jul). "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 1488965. PMID 16775335. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  9. Dingle K, Bichko V, Zuccola H, Hogle J, Taylor J (1998). "Initiation of hepatitis delta virus genome replication". J Virol. 72 (6): 4783–8. PMC 110015. PMID 9573243.
  10. Ryu WS, Bayer M, Taylor J (1992). "Assembly of hepatitis delta virus particles". J Virol. 66 (4): 2310–5. PMC 289026. PMID 1548764.
  11. Modahl LE, Lai MM (1998). "Transcription of hepatitis delta antigen mRNA continues throughout hepatitis delta virus (HDV) replication: a new model of HDV RNA transcription and replication". J Virol. 72 (7): 5449–56. PMC 110180. PMID 9621000.
  12. Fields, Bernard (2013). Fields virology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 1451105630.
  13. Sureau C, Taylor J, Chao M, Eichberg JW, Lanford RE (1989). "Cloned hepatitis delta virus cDNA is infectious in the chimpanzee". J Virol. 63 (10): 4292–7. PMC 251044. PMID 2778877.

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