Dependoparvovirus

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Dependoparvovirus
Adeno-associated viruses.jpg

Adeno-associated viruses

Systematics
Classification : Viruses
Area : Monodnaviria
Empire : Shotokuvirae
Phylum : Cossaviricota
Class : Quintoviricetes
Order : Piccovirales
Family : Parvoviridae
Subfamily : Parvovirinae
Genre : Dependoparvovirus
Taxonomic characteristics
Genome : ssDNA
Baltimore : Group 2
Symmetry : icosahedral
Cover : no
Scientific name
Dependoparvovirus
Short name
AAV
Left
NCBI  Taxonomy: 10803
ViralZone ( ExPASy , SIB): 226

Dependoparvovirus (formerly: Dependovirus , Adeno-associated virus group , AAV ) is a genus of Parvoviridae , a family of DNA viruses , subfamily Parvovirinae . The best-known representatives of the dependoparvoviruses are the adeno-associated virus (AAV) A and B. The replication of the dependoparvoviruses depends on a co-infection with a helper virus , which is where the name comes from. Adenoviruses or herpes viruses are usedas helper viruses.

properties

Virion

The virions (virus particles) of the dependoparvoviruses have an unenveloped icosahedral capsid about 22 nm in diameter. The capsid is made up of the three capsid proteins VP1–3 and consists of 60 proteins with a triangulation number of one. Each capsid has five VP1 proteins, five VP2 proteins and 50 VP3 proteins. This is where the single-stranded viral DNA is located .

Genome

The DNA genome is single-stranded 4.7 kilobases (Kb) in length with different polarity and has two open reading frames . At the 3 'end is the cap gene for the capsid proteins, which by alternative splicing results in the proteins VP1 or VP2 and VP3. The second gene rep codes for the replication-relevant proteins. Alternative splicing results in either Rep78, Rep68, Rep52 or Rep40, with the numbering being based on electrophoretic mobility . Six mRNAs are generated from the genome (4.2 Kb, 3.9 Kb, 3.6 Kb, 3.3 Kb, 2.6 Kb and 2.3 Kb in length), all of which have a poly-A tail .

The inverted repeats of about 145 bases at the ends of the genome form a T-shaped secondary structure due to the palindromic DNA sequence of the first 125 bases . The inverted repeat serves both as a starting point for replication and for the insertion of the viral DNA into the host's DNA on chromosome 19 . The complementary areas of the inverted repeat have a free hydroxyl group at the 3 'end for replication. The 3 'end is used as a primer for the synthesis of the leading strand , then double-stranded transition forms are formed.

Dependoparvoviruses are replication deficient by themselves, i.e. i.e., they need a helper virus. The proteins of the adenoviruses necessary for replication have been identified and are used for the production of dependoviral vectors . Furthermore, a replication of the dependoparvoviruses can also be triggered by UV radiation , cycloheximide , aphidicolin , topoisomerase inhibitors , hydroxyurea and various chemical carcinogens .

The insertion of the viral DNA takes place on chromosome 19, preferably in troponin genes. The genes contained are therefore increasingly read in muscle cells. The virus latency and persistent infection result from the insertion and genetic repression . Therefore, dependoparvoviruses are used as viral vectors in gene therapy, where long-term gene expression of the DNA of the recombinant protein in the vector without the production of viral proteins is desired. In addition, the genomes of some AAVs can also be present as episomes .

Proteome

The proteome of the dependoparvoviruses includes, among other things, the three structural proteins VP1–3 occurring in the virion and the non-structural proteins and helicases Rep78, Rep68, Rep52 or Rep40. Rep78 is a helicase and a repressor protein on the rep binding element (RBE) in the p5 promoter , as a result of which the production of Rep78 and Rep68 is largely stopped in the absence of a helper virus and the insertion takes place instead. Rep52 is a repressor on the p19 promoter, which controls the gene expression of Rep52 and Rep40.

Replication cycle

After the adsorption of virions to the cell membrane , the indentation is made by endocytosis . During the maturation of the endosome into a lysosome , the endosome membrane penetrates and the genome is released into the cytosol . The viral genome is introduced into the cell nucleus imported, after which the gene expression of rep is carried genes and replication of the viral genome via a double-stranded DNA intermediate is initiated. The components of the virion are completed by gene expression of the cap genes. Then the single-stranded DNA of positive or negative polarity is bound to the capsid proteins, whereby the virions join together. Dependoparvoviruses leave the cell after it has been destroyed by the lytic helper viruses.

Systematics

The genus dependoparvovirus includes:

  • Adeno-associated virus 1 to 4 (AAV-1 to AAV-4)
  • Adeno-associated virus 5 (AAV-5)

Host spectrum

Dependoparvoviruses are found in various vertebrates . They are mainly dependent on the presence of a helper virus. There are no infectious diseases associated with dependoparvovirus , and antibodies are formed when infected . More than 90% of adults are AAV seropositive , i. that is, they were or are infected with AAV.

Gene therapy

Various dependoparvoviruses integrate their viral DNA into the genome of their host, preferably in chromosome 19 , easing the likelihood of invading an important area that could disrupt normal gene function or increase the risk of cancer. Therefore Dependoparvoviren be as the AAV in gene therapy as a viral vector used as viral vectors Dependoparvoviren used have a relatively low DNA packaging capacity. The adeno-associated viral vectors have a maximum DNA length of eight kilobases (single-stranded), which can still be packaged in virions. If self-complementary DNA is used, the maximum length of a transgene is reduced to five kilobases, and the virus titer decreases with lengths above this . Work is underway to increase the amount of information this vector can provide. This may (by the ITRs English inverted terminal repeats ) can be achieved, which also are both the 5 'at the 3'-end of the genome. Since the ITRs have the same sequence, complementary strands remain free after their removal. The complementary strands can recombine and join two 5 kb inserted fragments together.

As with all viral vectors, antibodies against the viral proteins (in this case against capsid proteins ) arise in the context of innate and adaptive vector immunity . Therefore, to avoid premature degradation of the vector or excessive immune reactions, one serotype can only be used once per patient, so that new serotypes are continuously developed. However, insertions of AAV vectors have also been found in transcription-active regions of the genome outside the troponin genes, which can contribute to the development of tumors .

Web links

Commons : Dependovirus  - collection of images, videos and audio files

Individual evidence

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  13. ↑ Excoffon, K, et al. : Directed evolution from adeno-associated virus to an infectious respiratory virus . In: Proceedings on the National Academy of Science . 106, No. 10, 2009, pp. 3865-3870. doi : 10.1073 / pnas.0813365106 . PMID 19237554 . PMC 2646629 (free full text).
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