Hepatitis D Virus
Hepatitis D Virus On the Web
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Hepatitis D infection is caused by the hepatitis D virus.
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. 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. 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.
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.
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.
- Provision of appropriate metabolic conditions for the synthesis of viral macromolecules
- Final assembly of viral subunits
- 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. After entering the host cell, the virus loses its coat. 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.
- 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. The translation of the HDV mRNA yields:
- 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.
- 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
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.
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