Hepatitis D

Last updated
Hepatitis D
Other namesHepatitis delta
Specialty Infectious disease   OOjs UI icon edit-ltr-progressive.svg
SymptomsFeeling tired, nausea and vomiting [1]
Complications Cirrhosis [1]
CausesHepatitis D virus [1]
Diagnostic method Immunoglobulin G [2]
TreatmentPegylated interferon alpha [2]

Hepatitis D is a disease caused by the hepatitis delta virus (HDV), a small spherical enveloped virusoid. [3] 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). [4] Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).

Contents

Both superinfection and coinfection with HDV result 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. [5] In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.

Virology

Hepatitis delta virus
Hepatitis-d-virion-Pathogens-04-00046-g001-1024.png
Schematic representation of the Hepatitis delta virus virion
Virus classification Red Pencil Icon.png
(unranked): Virus
Realm: Riboviria
Phylum: incertae sedis
Genus: Deltavirus
Species:
Hepatitis delta virus
Isolates [6]
  • Hepatitis delta virus - 1 (USA, Europe, China)
  • Hepatitis delta virus - 2 (Japan)
  • Hepatitis delta virus - 3 (South America)
  • Hepatitis delta virus - 4 (Taiwan, Japan)
  • Hepatitis delta virus - 5 (Africa)
  • Hepatitis delta virus - 6 (Africa)
  • Hepatitis delta virus - 7 (Africa)
  • Hepatitis delta virus - 8 (Africa)

Structure and genome

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. [7] Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg. [8] [9] The hepatitis D circular genome is unique among animal viruses because of its high GC nucleotide content. The HDV genome exists as an 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. [10] 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. [11] [12]

Life cycle

Like hepatitis B, HDV gains entry into liver cells via the NTCP [13] bile transporter. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg. [14] Mapping by mutagenesis of this domain has shown that amino acid residues 9–15 make up the receptor-binding site. [15] After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg [16] Since the nucleocapsid does not contain an RNA polymerase to replicate the virus’ genome, the virus makes use of the cellular RNA polymerases. Initially thought to use just RNA polymerase II, [17] [18] now RNA polymerases I and III have also been shown to be involved in HDV replication. [19] 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.[ citation needed ]

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 polymerase I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA polymerase II. [20] 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. [21] [22]

Delta antigens

Hepatitis delta virus delta antigen
PDB 1a92 EBI.jpg
oligomerization domain of hepatitis delta antigen
Identifiers
SymbolHDV_ag
Pfam PF01517
InterPro IPR002506
SCOPe 1a92 / SUPFAM

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. [23] 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 UGG, allowing the large-HDAg to be produced. [23] [24] 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. [25] [26] [27] 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.

Antigenic loop infectivity

The HDV envelope protein has three of the HBV surface proteins anchored to it. The S region of the genome is most commonly expressed and its main function is to assemble subviral particles. HDV antigen proteins can combine with the viral genome to form a ribonucleoprotein (RNP) which when enveloped with the subviral particles can form viral-like particles that are almost identical to mature HDV, but they are not infectious. Researchers had concluded that the determinant of infectivity of HDV was within the N-terminal pre-S1 domain of the large protein (L). It was found to be a mediator in binding to the cellular receptor. Recently, researchers Georrges Abou Jaoudé and Camille Sureau published an article that studied the role of the antigenic loop, found in HDV envelope proteins, in the infectivity of the virus. The antigenic loop, like the N-terminal pre-S1 domain of the large protein, is exposed at the virion surface. Jaoudé and Sureau's study provided evidence that the antigenic loop may be an important factor in HDV entry into the host cell and by mutating parts of the antigenic loop, the infectivity of HDV may be minimized. [28]

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. [29] In all, about 20 million people may be infected with HDV. [30]

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. [31] [32]

In absence of a specific vaccine against delta virus, the vaccine against HBV must be given soon after birth in risk groups.[ citation needed ]

Treatment

Hepatitis D is generally considered the dominant virus over hepatitis B except in rare instances. Current established treatments for chronic hepatitis D include conventional or pegylated interferon alpha therapy. [33] 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. [34] The efficiency of this treatment does not usually exceed ~20%, and late relapse after therapy has been reported. [35] [36]

Epidemiology

Worldwide prevalence of HDV among HBV carriers in 2015. Eight genotypes have been identified worldwide by comparative phylogenetic analysis. Genotype 1 is the most frequent and has variable pathogenicity, Genotypes 2 and 4 are found in East Asia causing relatively mild disease. Genotype 3 is found in South America in association with severe hepatitis. Genotypes 5, 6, 7, 8 have been found only in Africa. Hep D Epidemiology Figure 1.svg
Worldwide prevalence of HDV among HBV carriers in 2015. Eight genotypes have been identified worldwide by comparative phylogenetic analysis. Genotype 1 is the most frequent and has variable pathogenicity, Genotypes 2 and 4 are found in East Asia causing relatively mild disease. Genotype 3 is found in South America in association with severe hepatitis. Genotypes 5, 6, 7, 8 have been found only in Africa.

Those afflicted are individuals who have been infected with Hepatitis B virus as the Hepatitis D (HDV) virus needs the HBsAg (hepatitis B surface antigen) to replicate. The disease is present worldwide. Infection with HDV is a major medical scourge in low income regions of the globe in which the HBV remains endemic.

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. [38] 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. [39] The entire genome was cloned and sequenced in 1986. It was subsequently placed in its own genus: Deltavirus. [40] [41]

Lábrea fever

Lábrea fever
Other namesLábrea's black fever, Lábrea hepatitis, Santa Marta fever
Specialty Infectious disease

Lábrea fever is a lethal tropical viral infection discovered in the 1950s in the city of Lábrea, in the Brazilian Amazon basin, where it occurs mostly in the area south of the Amazon River, in the states of Acre, Amazonas and Rondônia. The disease has also been diagnosed in Colombia and Peru. It is now known to be is a coinfection or superinfection of hepatitis B (HBV) with hepatitis D. [42]

Lábrea fever has a sudden onset, with jaundice, anorexia (lack of appetite), hematemesis (vomiting of blood), headache, fever and severe prostration. Death occurs by acute liver failure (ALF). In the last phase, neurological symptoms such as agitation, delirium, convulsions and hemorrhagic coma commonly appear. These symptoms arise from a fulminant hepatitis which may kill in less than a week, and which characteristically affects children and young adults, and more males than females. It is accompanied also by an encephalitis in many cases. The disease is highly lethal: in a study carried out in 1986 at Boca do Acre, also in the Amazon, 39 patients out of 44 died in the acute phase of the disease. [42] Survivors may develop chronic disease.

The main discovery of delta virus and HBV association was done by Gilberta Bensabath, of the Instituto Evandro Chagas, of Belém, state of Pará, and her collaborators.

Infected patients show extensive destruction of liver tissue, with steatosis of a particular type (microsteatosis, characterized by small fat droplets inside the cells), and infiltration of large numbers of inflammatory cells called morula cells, comprised mainly by macrophages containing delta virus antigens.

In the 1987 Boca do Acre study, scientists did an epidemiological survey and reported delta virus infection in 24% of asymptomatic HBV carriers, 29% of acute nonfulminant hepatitis B cases, 74% of fulminant hepatitis B cases, and 100% of chronic hepatitis B cases. The delta virus seems to be endemic in the Amazon region.

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). [43] Phylogenetic studies suggest an African origin for this pathogen. [29]

An analysis of 36 strains of genotype 3 estimated that the most recent common ancestor of these strains originated around 1930. [44] 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. Another study [45] found an overall evolution rate of 3.18 x 10×10−3 substitutions per site per year. The mutation rate varied with position : the hypervariable region evolved faster (4.55 x 10×10−3 substitutions per site per year) than the hepatitis delta antigen coding region (2.60 x 10×10−3 substitutions per site per year) and the autocatalytic region (1.11 x 10×10−3 substitutions per site per year). A third study suggested a mutation rate between 9.5x10×10−3 to 1.2x10×10−3 substitutions/site/year. [46]

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 Yakutia; 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. [47] 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. [48]

HDV-specific CD8+ T cells can control the virus, but it has been found HDV mutates to escape detection by CD8+ T cells. [49]

A similar virus has been described in ducks. [50] The protein encoded in the avian virus shares 32% homology with Hepatitis D.[ citation needed ]Another similar agent has been described in snakes. [51] It has been given the name Snake Hepatitis D virus.

Four additional viruses have been described: [52]

Related Research Articles

<i>Hepadnaviridae</i> family of viruses

Hepadnaviridae is a family of viruses. Humans, apes, and birds serve as natural hosts. There are currently over 12 species in this family, divided among 5 genera. Its best-known member is hepatitis B virus. Diseases associated with this family include: liver infections, such as hepatitis, hepatocellular carcinomas, and cirrhosis.

Picornavirus family of viruses

A picornavirus is a virus belonging to the family Picornaviridae, a family of viruses in the order Picornavirales. Vertebrates, including humans, serve as natural hosts. Picornaviruses are nonenveloped viruses that represent a large family of small, cytoplasmic, plus-strand RNA (~7.5kb) viruses with a 30-nm icosahedral capsid. Its genome does not have a lipid membrane. Picornaviruses are found in mammals and birds. There are currently 80 species in this family, divided among 35 genera. Notable examples are Enterovirus, Aphthovirus, Cardiovirus, and Hepatovirus genera. The viruses in this family can cause a range of diseases including paralysis, meningitis, hepatitis and poliomyelitis. Picornaviruses are in Baltimore IV class. Their genome single-stranded (+) sense RNA is what functions as mRNA after entry into the cell and all viral mRNA synthesized is of genome polarity. The mRNA encodes RNA dependent RNA polymerase. This polymerase makes complementary minus strands of RNA, then uses them as templates to make more plus strands. So, an overview of the steps in picornavirus replication are in order: attachment, entry, translation, transcription/genome replication, assembly and exit.

<i>Hepacivirus C</i> species of virus

Hepacivirus C (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The Hepacivirus C is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

<i>Rubella virus</i> species of virus

Rubella virus (RuV) is the pathogenic agent of the disease rubella, and is the main cause of congenital rubella syndrome when infection occurs during the first weeks of pregnancy.

Rabies virus species of virus

Rabies lyssavirus, formerly Rabies virus, is a neurotropic virus that causes rabies in humans and animals. Rabies transmission can occur through the saliva of animals and less commonly through contact with human saliva. Rabies lyssavirus, like many rhabdoviruses, has an extremely wide host range. In the wild it has been found infecting many mammalian species, while in the laboratory it has been found that birds can be infected, as well as cell cultures from mammals, birds, reptiles and insects.

A satellite is a subviral agent composed of nucleic acid that depends on the co-infection of a host cell with a helper virus for its replication.

<i>Lassa mammarenavirus</i> Type of viral hemorrhagic fever

Lassa mammarenavirus (LASV) is an arenavirus that causes Lassa hemorrhagic fever, a type of viral hemorrhagic fever (VHF), in humans and other primates. Lassa mammarenavirus is an emerging virus and a select agent, requiring Biosafety Level 4-equivalent containment. It is endemic in West African countries, especially Sierra Leone, the Republic of Guinea, Nigeria, and Liberia, where the annual incidence of infection is between 300,000 and 500,000 cases, resulting in 5,000 deaths per year.

Arenavirus genus of viruses

An arenavirus is a bisegmented ambisense RNA virus that is a member of the family Arenaviridae. These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenaviruses, have also been discovered which infect snakes to produce inclusion body disease. At least eight arenaviruses are known to cause human disease. The diseases derived from arenaviruses range in severity. Aseptic meningitis, a severe human disease that causes inflammation covering the brain and spinal cord, can arise from the lymphocytic choriomeningitis virus. Hemorrhagic fever syndromes, including Lassa fever, are derived from infections such as Guanarito virus, Junin virus, Lassa virus, Lujo virus, Machupo virus, Sabia virus, or Whitewater Arroyo virus. Arenaviruses are divided into two groups: the Old World and the New World viruses. The differences between these groups are distinguished geographically and genetically. Because of the epidemiological association with rodents, some arenaviruses and bunyaviruses are designated as roboviruses.

The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine (mouse) hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses. Replicating MLVs have a positive sense, single-stranded RNA (ssRNA) genome that replicates through a DNA intermediate via the process of reverse transcription.

A helper dependent virus also termed a gutless virus is a synthetic viral vector dependent on the assistance of a helper virus in order to replicate.

Hepatitis delta virus ribozyme

The hepatitis delta virus (HDV) ribozyme is a non-coding RNA found in the hepatitis delta virus that is necessary for viral replication and is the only known human virus that utilizes ribozyme activity to infect its host. The ribozyme acts to process the RNA transcripts to unit lengths in a self-cleavage reaction during replication of the hepatitis delta virus, which is thought to propagate by a double rolling circle mechanism. The ribozyme is active in vivo in the absence of any protein factors and was the fastest known naturally occurring self-cleaving RNA at the time of its discovery.

Hepatitis B human viral infection

Hepatitis B (HB) is an infectious disease caused by the hepatitis B virus (HBV) that affects the liver. It can cause both acute and chronic infection. Many people have no symptoms during the initial infection. In acute infection, some may develop a rapid onset of sickness with vomiting, yellowish skin, tiredness, dark urine and abdominal pain. Often these symptoms last a few weeks and rarely does the initial infection result in death. It may take 30 to 180 days for symptoms to begin. In those who get infected around the time of birth 90% develop chronic hepatitis B while less than 10% of those infected after the age of five do. Most of those with chronic disease have no symptoms; however, cirrhosis and liver cancer may eventually develop. Cirrhosis or liver cancer occur in about 25% of those with chronic disease.

HBx hepatitis B viral protein

HBx is a hepatitis B viral protein. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. It interacts with DDB1 redirecting the ubiquitin ligase activity of the CUL4-DDB1 E3 complexes, which are intimately involved in the intracellular regulation of DNA replication and repair, transcription and signal transduction.

<i>Hepatitis B virus</i> species of the genus Orthohepadnavirus

Hepatitis B virus, abbreviated HBV, is a partially double-stranded DNA virus, a species of the genus Orthohepadnavirus and a member of the Hepadnaviridae family of viruses. This virus causes the disease hepatitis B.

The transmission of hepadnaviruses between their natural hosts, humans, non-human primates, and birds, including intra-species host transmission and cross-species transmission, is a topic of study in virology.

Hepatitis B virus precore mutant variety of hepatitis B virus

A precore mutant is a variety of hepatitis B virus that does not produce hepatitis B virus e antigen (HBeAg). These mutants are important because infections caused by these viruses are difficult to treat, and can cause infections of prolonged duration and with a higher risk of liver cirrhosis. The mutations are changes in DNA bases from guanine to adenine at base position 1896 (G1896A), and from cytosine to thymine at position 1858 (C1858T) in the precore region of the viral genome.

Picornain 3C class of enzymes

Picornain 3C (EC 3.4.22.28, Picornain 3C is a protease and endopeptidase enzyme found in the picornavirus, that cleaves peptide bonds of non- terminal sequences. Picornain 3C’s proteinase activity is primarily responsible for the catalytic process of selectively cleaving Gln-Gly bonds in the polyprotein of poliovirus and substitution of Glu for Gln, and Ser or Thr for Gly in other picornaviruses. Picornain 3C are cysteine proteases related by amino acid sequence to trypsin-like serine proteases. Picornain 3C is encoded by enteroviruses, rhinoviruses, aphtoviruses and cardioviruses. These genera all cause a wide range of infections for humans and other mammals.

Positive-sense single-stranded RNA virus Class of viruses in the Baltimore classification

A positive-sense single-stranded RNA virus is a virus that uses positive sense single stranded RNA as its genetic material. Single stranded RNA viruses are classified as positive or negative depending on the sense or polarity of the RNA. The positive-sense viral RNA genome can serve as messenger RNA and can be translated into protein in the host cell. Positive-sense ssRNA viruses belong to Group IV in the Baltimore classification. Positive-sense RNA viruses account for a large fraction of known viruses, including many pathogens such as the hepacivirus C, West Nile virus, dengue virus, SARS and MERS coronaviruses, and SARS-CoV-2 as well as less clinically serious pathogens such as the rhinoviruses that cause the common cold.

Ground squirrel hepatitis virus species of virus

Ground squirrel hepatitis virus, abbreviated GSHV, is a partially double-stranded DNA virus that is closely related to human Hepatitis B virus

<i>Woolly monkey hepatitis B virus</i> species of virus

The woolly monkey hepatitis B virus (WMHBV) is a viral species of the Orthohepadnavirus genus of the Hepadnaviridae family. Its natural host is the woolly monkey (Lagothrix), an inhabitant of South America categorized as a New World primate. WMHBV, like other hepatitis viruses, infects the hepatocytes, or liver cells, of its host organism. It can cause hepatitis, liver necrosis, cirrhosis, and hepatocellular carcinoma. Because nearly all species of Lagothrix are threatened or endangered, researching and developing a vaccine and/or treatment for WMHBV is important for the protection of the whole woolly monkey genus.

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Bibliography

Classification
D