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Understanding hepatitis D

?What is the mechanism of action of the HDV?

Hepatitis D virus (HDV) is a defective virus that is dependent on hepatitis B virus (HBV) for its mechanism of action in order to assemble and release the virus. Indeed, HDV does not code for its own envelope proteins and strictly depends on the expression of the hepatitis B virus surface antigen to:

  • infect human hepatocytes,
  • ensure its viral assembly,
  • complete its viral life cycle (1).
HDV dependance on HBV
From Mentha et al. 2019

VHD viral particle

The HDV viral particle is about 36 nm in diameter and contains the single-stranded, circular RNA genome.

The RNA viral genome has 70% sequence complementarity allowing its folding into a rod-like structure. In association with the delta antigen (HDAg), the viral RNA is encapsudated into viral ribonucleoprotein (RNP) (1,2).

VHD viral particle representation

The mechanism of the viral replication cycle

IN GENERAL (1)

1/ Binding and entry:
Also called viral entry, this step leads to the release of the viral genome into the target cell.

2/ Gene expression and replication:
This step ensures the synthesis of proteins encoded by the viral genome and allows the multiplication of this genome.

3/ Assembly and release:
The release of infectious viral particles enables the infection to spread to other cells.

HDV LIFE CYCLE

HDV is considered to enter hepatocytes through the same mechanism of action as HBV, given that both viruses share a similar envelope.

The first step consists in the attachment of the virion to the heparan sulfate proteoglycans (HSPGs) exposed on the outer face of the host cell membrane (2).

In order for it to be able to penetrate the cell, a further interaction of the virus with its specific NTCP receptor (NTCP = sodium taurocholate co-transporting polypeptide), a bile acid transporter that is only expressed on hepatocytes, is necessary.(3)(4)
Viruses can only replicate within living cells and their life cycle is complex, HDV is no exception. The interaction between the viral genome and the host cell results in the production of new viral particles. So, the HDV replicative cycle can be described as below (1):

The mechanism of the Hepatitis D viral (HDV) replication cycle
  1. Viral Entry of HDV into the target cell through interaction with the NTCP receptor.
  2. Transport of the viral ribonucleoprotein (RNP) into the nucleus where the viral genome is released.
  3. HDV mRNA transcription from the viral genome used as a template.
  4. Translation of viral mRNA into proteins by the cellular machinery.
  5. Viral RNA replication using the cellular machinery.
  6. Assembly of viral proteins with the (newly synthesized) viral RNA to form the RNP, the replicative entity of HDV.
  7. Export of RNP out of the nucleus and association with HBV surface proteins
  8. Release of HDV and HBV viral particles first from the Golgi apparatus and then from the cell.

Sources

  1. Mentha N et al. A review on hepatitis D: From virology to new therapies. Journal of Advanced Research 2019; 17: 3-15.
  2. Wedemeyer H. Manns MP, Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat. Rev. Gastroenterol. Hepatol. 2010; 7: 31-40.
  3. Ni Y et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology. 2014 Apr; 146 (4): 1070-83.
  4. Yan H et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012 Nov 13