Hepatitis B virus

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Hepatitis B virus
Hepatitis B virus 01.jpg

Hepatitis B virus

Systematics
Classification : Viruses
Area : Riboviria
Empire : Pararnavirae
Phylum : Artverviricota
Class : Revtraviricetes
Order : Blubervirales
Family : Hepadnaviridae
Genre : Orthohepadna virus
Type : Hepatitis B virus
Taxonomic characteristics
Genome : dsDNA
Baltimore : Group 7
Symmetry : icosahedral
Cover : available
Scientific name
Hepatitis B virus
Short name
HBV
Left
NCBI  Taxonomy: 10407
ICTV Taxon History: 201853653

The hepatitis B virus (HBV) is an enveloped DNA virus with a predominantly double-stranded genome and the trigger of the Hepatitis B . The hepatitis B virus comes from the genus Orthohepadnaviruses within the family of the Hepadnaviridae .

illness

In addition to hepatitis B, HBV causes cirrhosis and liver cancer in chronic courses . There may also be a connection in pancreatic cancer . The hepatitis B virus does not have a cytopathic effect , so the damage to the liver cells is increasingly attributed to the immune reaction (indirect pathogenesis , immunopathogenesis ). Through the continuous growth stimulation to replace the infected hepatocytes destroyed by the immune system and through the cytokines , some of which have growth-promoting properties, and through the partial insertion into the cellular DNA, more copying errors occur in the DNA during mitosis (in the S phase), which is what leads to the formation favored by tumors .

construction

Schematic structure of the HBV.

The virion has a virus envelope and an icosahedral capsid . The capsid encloses the viral DNA and a DNA polymerase with a reverse transcriptase activity (RT), similar to a retroviral polymerase. The virus envelope contains HBsAg and the pre-S1 protein as membrane protein for binding to the host cell . With a diameter of 42 nm, the spherical HBV (also called Dane particle ) is one of the smaller animal viruses. There are also non-infectious filamentous and spherical forms without capsid with a diameter of 20 nm, since HBsAg is formed in excess. These virosomes consist of HBsAg in a lipid bilayer . Because of their immunogenicity with no infectivity, they were used in the early hepatitis B vaccines . With recombinant expression (without HBsAg) the HBcAg can also form virosomes.

HBV reaches a virus concentration between 10 4 and 10 9 virions per milliliter in the blood , the virosomes from HBsAg even reach particle concentrations of up to 10 12 particles per milliliter.

Genome

The HBV genome. The genes overlap.

The HBV genome consists of circularly closed DNA , but the DNA is not completely double-stranded and one strand is continuous. One end of the continuous strand of around 3020–3320 nucleotides binds the viral DNA polymerase, while the shorter strand with 1700 to 2800 nucleotides is significantly shorter.

The continuous (-) strand (non-coding) is reverse complementary to the viral mRNA . The viral DNA can be detected in the cell nucleus shortly after infection . The partially double-stranded DNA is completed on the (+) strand and an RNA sequence on the (+) strand is removed. Finally, overhanging nucleotides are removed and the (-) strand closed to form a ring.

The four genes of HBV are called C ( core ), X, P ( polymerase ) and S ( surface ). The core protein HbcAg is produced from a preprotein by proteolysis . The S gene of the HBsAg protein contains three start codons (AUG) that conform to the reading frame , resulting in three proteins, pre-S1 (synonymous L), pre-S2 (synonymous M) and S.

Various non-coding RNAs have been identified in the HBV genome. These are referred to as Hepatitis B virus PRE alpha , Hepatitis B virus PRE beta and HBV RNA encapsidation signal epsilon .

Proteins

The HBV virion consists of four structural proteins; HBeAg also occurs outside the virion.

HBsAg

Virus-like particles from HBsAg

HBsAg ( English HBV surface antigen , HBV surface antigen ) is a surface protein of the virion that is recognized as an antigen by antibodies in the course of the immune reaction . It can be detected in the blood of infected people through virological diagnostics and shows when a patient is no longer contagious. In histology, HBsAg is detected by a Shikata orcein stain .

Historically, HBsAg was first known as the Australia Antigen , as it was first discovered in the blood serum of Australian Aborigines by Baruch Samuel Blumberg . Alfred Prince discovered the connection with a form of hepatitis in 1968. The first vaccine against HBV ( Heptavax ) was purified from the blood plasma of those infected with HBV ; due to the risk of contamination by other pathogens , it was later switched to recombinant proteins from baker's yeast .

The hepatitis D virus needs HBsAg to become pathogenic.

HBcAg

HBcAg ( English core antigen , antigen of the virus core ) is used to package the viral DNA and is used to detect a current infection. It is the capsid protein of HBV.

HBeAg

HBeAg ( English extracellular antigen , extracellular antigen) is a splice variant from the open reading frames core-ORF and pre-C-ORF . HBeAg is secreted and is not found in the virion. Like HBcAg, HBeAg is used to detect a current infection. Presumably it serves to reduce the gene expression of toll-like receptor 2 on hepatocytes and monocytes and thus to dampen the immune response against HBV. HBeAg is not essential, ie virions without HBeAg expression are infectious and pathogenic.

Hepatitis B virus DNA polymerase

The DNA polymerase of the HBV is the replication of the viral genome. Lamivudine and penciclovir inhibit polymerase in non-resistant HBV strains.

HBx

Little is known about the function of the X protein. The X protein may be derived from a DNA glycosylase . HBx increases the release of calcium ions from the mitochondria . The HBx changes cellular transcription , the cell cycle and forms a protein complex with the cellular protein HBX interacting protein (HBXIP), which interacts with the spindle apparatus during cell division . HBx also interacts with Damaged DNA Binding Protein 1 (DDB1) and inhibits the CUL4 -DDB1- E3 complexes and thereby the ubiquitin-proteasome system . HBx promotes cell division and thereby promotes the development of tumors. HBx inhibits the protein arginine methyltransferase PRMT1, which increases the replication of HBV.

Occurrence and genotypes

Global distribution of HBV in humans

The reservoir host of HBV is mainly the person next to HBV also comes in great apes and gibbons before. The eight genotypes of HBV are named A to H. A genotype I may also exist, but this is not unanimously accepted. The different genotypes respond differently to therapies.

The genotypes differ by at least eight percent at the genome level and have different geographical frequencies. Genotype F differs the most from the others, with a fourteen percent difference. Genotype A is prevalent in Europe , Africa, and South Asia , including the Philippines . Genotypes B and C are predominant in Asia ; the genotype D occurs in the Mediterranean region , the Middle East and India . Genotype E exists in sub- Saharan Africa . The genotype F (or H) occurs in Central and South America . Genotype G was found in France and Germany . Genotypes A, D, and F dominate in Brazil, and all genotypes occur with ethnic clusters in the United States .

Within the genotypes, 24 subtypes are described, which differ from one another in their DNA sequence by four to eight percent.

  • Genotype A has two subtypes: Aa (A1) in Africa / Asia and Ae (A2) in Europe / USA.
  • Genotype B has two geographically separated subtypes: Bj / B1 ('j' - Japan) and Ba / B2 ('a' - Asia). The genotype Ba is further divided into four clades (B2 - B4).
  • Genotype C also has two geographically separated subtypes: Cs (C1) in Southeast Asia and Ce (C2) in East Asia. The C subtype is divided into five clades , while a possible sixth (C6) and a seventh (C7) have so far only been found in one isolate in the Philippines and West Papua. The genotype C1 occurs in Vietnam , Myanmar and Thailand . The genotype C2 occurs in Japan , Korea and China . The C3 genotype is found in New Caledonia and Polynesia . The genotype C4 occurs in Australia and C5 in the Philippines .
  • Genotype D is divided into seven subtypes (D1 - D7).
  • Genotype E has only one subtype.
  • Genotype F is divided into four subtypes (F1 - F4). The subtype F1 is further separated into clades 1a and 1b. In Venezuela , the subtypes F1, F2 and F3 are found in the west and east, while F3 occurs alone in the south. Subtype Ia occurs in Central America, subtype III in northern South America and IV in southern South America. The clade Ib is found in almost the entire American continent (except northern South America ) and the clade II is found in Central and South America.

evolution

The exact determination of the early evolution of HBV is problematic. The splitting of the hepadnaviruses into ortho- and avihepadnaviruses took place approximately 125,000 years ago (95% interval 78,297-313,500). Both avi and ortho hepadnaviruses began to change more rapidly around 25,000 years ago. At this time the division into the eight genotypes took place. Human hepadnaviruses separated approximately 7,000 (95% interval: 5.287–9.270) to 10,000 years (95% interval: 6.305–16.681). The avihepadnaviruses lack the X protein, but residues can still be found in the duck hepadna virus. The rate of non-synonymous HBV mutations was estimated to be about 2 × 10 −5 amino acid substitutions per site per year. The mean frequency of nucleotide substitutions per site per year was estimated at about 7.9 × 10 −5 . Another estimate suspects the last common ancestor of the human HBV strains 1,500 years ago and a separation from the avihepadnaviruses 6,000 years ago with a mutation rate of about 10 −6 substitutions per site per year.

Classification

HBV is a typical representative of the genus Orthohepadnaviruses , which has three other representatives: the Ground squirrel hepatitis virus , the Woodchuck hepatitis virus , and the Woolly monkey hepatitis B virus . The family of the Hepadnaviridae contains two other genera, the Avihepadnaviruses and one to be named. The family is not yet assigned to any order. HBV-like viruses have already been found in all Old World monkeys ( orangutans , gibbons , gorillas and chimpanzees ) and also in New World monkeys such as the woolly monkey , which suggests that this virus originated in primates.

HBV are divided into four serotypes (adr, adw, ayr, ayw), depending on the antigenic epitopes on their coat proteins, genetically they are assigned to eight genotypes (A – H) depending on their mutations . The individual genotypes have a different geographical distribution and are used for the epidemiological determination of transmission and viral evolution. The different genotypes also show differences in the course of the disease , the frequency of complications and in the choice of therapy and vaccine .

Replication cycle

Replication of the hepatitis B virus

The replication cycle of HBV:

  • Low affinity attachment ( adsorption ) to the cell membrane via glycosamine glycans, then binding to NTCP (Na + -taurocholate cotransporting polypeptide) and subsequent endocytosis via a previously unexplained mechanism.
  • Penetration (engl. Penetration or uncoating ) by an induced fusion of the viral envelope and the endosomal membrane , whereby the core with the DNA of the virus into the cytosol is liberated.
  • Unzip (Engl. Uncoating ) and transport in the cell nucleus via chaperones . This releases the DNA from the core and then completes the (-) strand and closes the ring to form the cccDNA , which is used as a template for the transcription of the four viral mRNAs (Pre-S1 / L, Pre-S2 / M, S and X) and the two RNAs used for expression and genome synthesis (C / P and Pre-C). All viral RNAs have a cap structure and a poly A tail .
  • Replication (engl. Replication ) in the cytosol, in which the longest RNA (C / P is longer than the viral DNA genome) serves as a template for the synthesis of the viral DNA genome, as well as protein biosynthesis of the capsid and the viral polymerase. The RNA intermediate increases the mutation rate to generate escape mutations . The cccDNA is imported into the cell nucleus up to the point in time of the synthesis of the envelope proteins HBcAg and HBsAg (after replication); the cccDNA is only exported from the cell nucleus through the envelope proteins. Due to the core import of the genome, the retention of unpackaged viral genomes in the cell nucleus results in the occasional persistent infection .
  • Assembly (engl. Assembly ) of the new virions following the pinch-a from the cell or transported back to the cell nucleus where the DNA is separated from the HBcAg and a new genome synthesis begins.
  • Release (engl. Budding, release ) of the Tochtervirionen by exocytosis (non- lytic ) with simultaneous synthesis of the DNA genome in the cytoplasm of the longest mRNA by the RT activity of the viral polymerase .

Environmental stability

As an enveloped virus, the hepatitis B virus is sensitive to chemical or physical disinfection processes , but due to the high protein content in the virus envelope, it is only inactivated relatively slowly by alcohols or surfactants compared to other enveloped viruses . The inactivation of HBV by disinfection procedure can with the MAD-test to be determined.

Reporting requirement

In Germany, any direct or indirect evidence of the hepatitis B virus must be reported by name in accordance with Section 7 of the Infection Protection Act .

In Switzerland, the positive laboratory analytical finding is a hepatitis B virus notifiable and that after the Epidemics Act (EpG) in connection with the epidemic Regulation and Annex 3 of the Regulation of EDI on the reporting of observations of communicable diseases of man .

literature

Individual evidence

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