Replication of parvoviruses

The parvoviruses are very small, nonenveloped, icosahedral viruses. Two of the three known groups infect warm-blooded animals while the third group has members that infect insects. The parvovirus capsid diameter is 26-30 nm, significantly smaller than the polyomaviruses even though the viral genome is approximately 5 kb long. The virus is able to package the genome into such a small virion because the virus encodes only a single DNA strand. Interestingly, many parvoviruses can package the DNA strand of sense either opposite to mRNA or equivalent to mRNA in equal or nearly equal numbers. This means that the packaging signals utilized by the virus to encapsidate the genome must occur on both strands - this is probably through the interaction of the unique end structures of both strands with capsids proteins.

The genome of adeno-associated virus, a typical parvovirus, is shown in Fig. 16.9. It encodes two protein translational reading frames that are expressed by a variety of transcripts. The first reading frame encodes nonstructural protein involved in replication, and the second encodes the capsid protein. The genome ends contain 120-300 bases of inverse repeated sequences so that they can form hairpin loops in solution and in the infected cell's nucleus. These terminal

Adeno-associated virus genome (5,000 nt)

Hairpin loops

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REP CAP

Fig. 16.9 The 5000-nucleotide (nt) linear genome of adeno-associated virus (AAV). This ssDNA has repeated sequences on both ends that allow it to form a "hairpin" structure. This serves as the template for conversion into dsDNA by cellular enzymes. Cellular enzymes also mediate replication of the viral genome. Three families of coterminal mRNAs are expressed from the three AAV promoters; the genome encodes replication proteins and a capsid protein but depends on cell replication for its ability to replicate its genome. This cellular replication is induced by a helper virus such as adenovirus in the animal, but the virus can replicate in cultures of some actively replicating cells. Other groups of parvoviruses, such as minute virus of mice (MVM), are able to replicate in some actively replicating cells of their natural host.

hairpins serve as primers for initiation of DNA replication, and since they are repeated at the ends of both (+) and (—) sense DNA strands, both can serve as templates for DNA replication.

Parvovirus replication is absolutely dependent on the host cell undergoing DNA replication. Thus, the virus can only replicate in actively replicating cells. Despite this, and unlike papova-viruses and adenoviruses, parvovirus has no ability to stimulate cell division via the action of a viral-encoded protein. This inability results in a very tight restriction of virus replication in the host's dividing cells, especially cells of the immune system. This can be devastating to young animals and parvovirus infection of dogs is a major problem in kennels. Parvovirus infection can also be very destructive to actively growing cells in adult animals. For example, feline panleukopenia, a parvovirus disease characterized by destruction of the immune system, is a significant pathogen of domestic cats.

Upon infection, the ssDNA is converted into full dsDNA by cellular DNA repair enzymes following its entry into the nucleus. The double-stranded viral DNA template is transcribed into a number of 3'-coterminal transcripts from one of three viral promoters just 5' of the transcript starts. Some of these transcripts are spliced, so each translational reading frame is translated into several proteins of related sequence. As noted previously, viral genome replication can only take place in cells in which there is active cellular DNA replication (i.e., in the S phase of cell division). The viral replication enzyme is involved in cleavage of the covalently closed replicating viral DNA into single-stranded genomic DNA and has no polymerase activity.

Dependovirus DNA integrates in a specific site in the host cell genome

Adeno-associated virus is representative of one major group of parvoviruses, the dependovi-ruses. It is usually found associated with active infections of adenoviruses and occasionally, with herpesviruses. The human parvovirus, adeno-associated virus (AAV), is a well-characterized example. While the dependoviruses can be grown in culture in fetal cells or following proper chemical stimulation of some adult host cells, they depend on the adenovirus or herpesvirus helpers to stimulate the cell in such a way that they can divide. Thus, like viroids, these viruses are parasitic on other viruses.

The dependence on a helper virus might be expected to be a great impediment to virus replication for AAV, but this is overcome in part by its ability to integrate into chromosome 19 of the host when it infects a cell in the absence of the helper. The integrated viral DNA allows AAV to remain latent in host tissue for long periods of time, but to "reactivate" if and when that cell is infected with a virus that can act as a helper.

Integration takes place at short stretches of homologous sequences within a region of several hundred bases in the host chromosome. While it allows the viral genome to remain associated with the host for long periods, integrated viral DNA serves as a biological "time bomb" — ready to replicate and kill the cell when it is infected with the appropriate helper. Since the replication of AAV interferes with the efficiency of replication of the helper virus, it may be that this process has the ultimate effect of limiting infection of the helper, thus providing some benefit to the host!

Parvoviruses have potentially exploitable therapeutic applications

The strict requirement for actively replicating cells, and the competition between AAV and adenovirus and herpesvirus infections, suggest that such viruses might be exploitable as antiviral or anticancer agents. Laboratory studies showed this to be feasible. For example, breeds of laboratory mice have high occurrences of certain tumors. Infection of young mice with minute virus of mice (MVM), a murine parvovirus, results in a significant increase in the animal's life span and fewer occurrences of tumors at young ages! It should be clear, however, that an effective application of such a result to human cancers is not a straightforward undertaking.

Another potential use for parvoviruses stems from their ability to integrate in a specific site in the chromosome. This integration is mediated by the hairpin loop ends of the viral genome, and may be useful in designing viral vectors for delivering genes into cells.

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  • Vivaldo
    Why does parvovirus need actively growing cells for replication?
    4 years ago

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