Hepatitis D
Encyclopedia
Hepatitis D, also referred to as hepatitis D virus (HDV) and classified as Hepatitis delta virus, is a disease
caused by a small circular enveloped RNA virus
. It 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). 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 chance of developing liver cancer
in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.
region at the N terminus of HDAg. 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
nucleotide sequence is 70% self-complementary, allowing the genome to form a partially double stranded RNA structure that is described as rod-like. 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 viruses called viroids.
There are at least 8 genotypes of this virus (HDV-1 to HDV-8).
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 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 nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II. 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 that acts as a ribozyme, which self-cleaves the linear RNA into monomers. This monomers are then ligated to form circular RNA
There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity.
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. 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.
, 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. In all, about 20 million people may be infected with HDV.
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
caused by a small circular enveloped RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
. It is one of five known hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
viruses: A
Hepatitis A
Hepatitis A is an acute infectious disease of the liver caused by the hepatitis A virus , an RNA virus, usually spread the fecal-oral route; transmitted person-to-person by ingestion of contaminated food or water or through direct contact with an infectious person...
, B, C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
, D, and E
Hepatitis E
Hepatitis E is a viral hepatitis caused by infection with a virus called hepatitis E virus . HEV is a positive-sense single-stranded RNA icosahedral virus with a 7.5 kilobase genome. HEV has a fecal-oral transmission route. It is one of five known hepatitis viruses: A, B, C, D, and E...
. HDV is considered to be a subviral satellite
Satellite (biology)
A satellite is a subviral agent composed of nucleic acid that depends on the co-infection of a host cell with a helper or master virus for its multiplication. When a satellite encodes the coat protein in which its nucleic acid is encapsidated it is referred to as a satellite virus...
because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection
Coinfection
In parasitology, coinfection is the term used to describe the simultaneous infection of a host by multiple pathogen species. In virology, coinfection can also refer to the simultaneous infection of a single cell by two or more virus particles...
) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection
Superinfection
In virology, superinfection is the process by which a cell, that has previously been infected by one virus, gets coinfected with a different strain of the virus, or another virus at a later point in time. Viral superinfections of serious conditions can lead to resistant strains of the virus, which...
).
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
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, with an increased chance of developing liver cancer
Liver cancer
Liver tumors or hepatic tumors are tumors or growths on or in the liver . Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. These growths can be benign or malignant...
in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections of 20%.
History
Hepatitis D virus was first reported in the mid-1970s, as a nuclear antigen in patients infected with HBV who had severe liver disease 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 The entire virus was cloned and sequenced in 1986, and obtained its own genus deltavirusStructure and Genome
The HDV is a small, spherical virus with a 36 nm diameter. It has an outer coat containing three HBV envelope proteins (called 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. Several interactions are also mediated by a coiled-coilCoiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...
region at the N terminus of HDAg. 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
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
nucleotide sequence is 70% self-complementary, allowing the genome to form a partially double stranded RNA structure that is described as rod-like. 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 viruses called viroids.
There are at least 8 genotypes of this virus (HDV-1 to HDV-8).
Life Cycle
The receptor that HDV recognizes on human hepatocytes has not been identified; however it is thought to be the same as the HBV receptor because both viruses have the same outer coat. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg. Mapping by mutagenesis of this domain has shown that aminoacid residues 9-15 make up the receptor binding site. After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg 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, now RNA polymerases I and III have also been shown to be involved in HDV replicationNormally 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 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 nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II. 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 that acts as a ribozyme, which self-cleaves the linear RNA into monomers. This monomers are then ligated to form circular RNA
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, HDAg is the only protein known to be coded for by the HDV genome. It consist of 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. 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 producedDespite 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. 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 countriesDeveloped country
A developed country is a country that has a high level of development according to some criteria. Which criteria, and which countries are classified as being developed, is a contentious issue...
, and is mostly associated with intravenous drug use
Drug injection
In substance dependence and recreational drug use, drug injection is a method of introducing a drug into the body with a hollow needle and a syringe which is pierced through the skin into the body...
. However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. In all, about 20 million people may be infected with HDV.
See also
- Hepatitis AHepatitis AHepatitis A is an acute infectious disease of the liver caused by the hepatitis A virus , an RNA virus, usually spread the fecal-oral route; transmitted person-to-person by ingestion of contaminated food or water or through direct contact with an infectious person...
- Hepatitis B and Hepatitis B in ChinaHepatitis B in ChinaHepatitis B is endemic in China. Of the 350 million individuals worldwide infected with the hepatitis B virus , one-third reside in China. As of 2006 China has immunized 11.1 million children in its poorest provinces as part of several programs initiated by the Chinese government and as part of the...
- Hepatitis CHepatitis CHepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
- Hepatitis EHepatitis EHepatitis E is a viral hepatitis caused by infection with a virus called hepatitis E virus . HEV is a positive-sense single-stranded RNA icosahedral virus with a 7.5 kilobase genome. HEV has a fecal-oral transmission route. It is one of five known hepatitis viruses: A, B, C, D, and E...
- Hepatitis FHepatitis FHepatitis F is a hypothetical virus linked to hepatitis. Several hepatitis F candidates emerged in the 1990s; none of these reports have been substantiated....
- Hepatitis G
External links
- World Health OrganizationWorld Health OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
Fact sheet on Hepatitis D - Viralzone: Deltavirus