Parvoviruses are a family of animal viruses that constitute the family Parvoviridae. They have linear, single-stranded DNA (ssDNA) genomes that typically contain two genes encoding for a replication initiator protein, called NS1, and the protein the viral capsid is made of. The coding portion of the genome is flanked by telomeres at each end that form into hairpin loops that are important during replication. Parvovirus virions are small compared to most viruses, at 23–28 nanometers in diameter, and contain the genome enclosed in an icosahedral capsid that has a rugged surface.
Parvoviruses enter a host cell by endocytosis, travelling to the nucleus where they wait until the cell enters its replication stage. At that point, the genome is uncoated and the coding portion is replicated. Viral messenger RNA (mRNA) is then transcribed and translated, resulting in NS1 initiating replication. During replication, the hairpins repeatedly unfold, are replicated, and refold to change the direction of replication to progress back and forth along the genome in a process called rolling hairpin replication that produces a molecule containing numerous copies of the genome. Progeny ssDNA genomes are excised from this concatemer and packaged into capsids. Mature virions leave the cell by exocytosis or lysis.
Parvoviruses are believed to be descended from ssDNA viruses that have circular genomes that form a loop because these viruses encode a replication initiator protein that is related to NS1 and have a similar replication mechanism. Another group of viruses called bidnaviruses appear to be descended from parvoviruses. Within the family, six subfamilies and 30 genera are recognized. Parvoviridae is the sole family in the order Piccovirales, which is the sole order in the class Quintoviricetes. This class is assigned to the phylum Cossaviricota, which also includes papillomaviruses, polyomaviruses, and bidnaviruses.
A variety of diseases in animals are caused by parvoviruses. Notably, the canine parvovirus and feline parvovirus cause severe disease in dogs and cats, respectively. In pigs, the porcine parvovirus is a major cause of infertility. Human parvoviruses are less severe, the two most notable being parvovirus B19, which causes a variety of illnesses including fifth disease in children, and human bocavirus 1, which is a common cause of acute respiratory tract illness, especially in young children. In medicine, recombinant adeno-associated viruses (AAV) have become an important vector for delivering genes to the cell nucleus during gene therapy.
Animal parvoviruses were first discovered in the 1960s, including minute virus of mice, which is frequently used to study parvovirus replication. Many AAVs were also discovered during this time period and research on them over time has revealed their benefit as a form of medicine. The first pathogenic human parvovirus to be discovered was parvovirus B19 in 1974, which became associated with various diseases throughout the 1980s. Parvoviruses were first classified as the genus Parvovirus in 1971 but were elevated to family status in 1975. They take their name from the Latin word parvum, meaning 'small' or 'tiny', referring to the small size of the virus's virions.
Genome
Parvoviruses have linear, single-stranded DNA (ssDNA) genomes that are about 4–6 kilobases (kb) in length. The parvovirus genome typically contains two genes, termed the NS/rep gene and the VP/cap gene. The NS gene encodes the non-structural (NS) protein NS1, which is the replication initiator protein, and the VP gene encodes the viral protein (VP) that the viral capsid is made of. NS1 contains an HUH superfamily endonuclease domain near its N-terminus, containing both site-specific binding activity and site-specific nicking activity, and a superfamily 3 (SF3) helicase domain toward the C-terminus. Most parvoviruses contain a transcriptional activation domain near the C-terminus that upregulates transcription from viral promoters as well as alternate or overlapping open reading frames that encode a small number of supporting proteins involved in different aspects of the viral life cycle.
The coding portion of the genome is flanked at each end by terminal sequences about 116–550 nucleotides (nt) in length that consist of imperfect palindromes folded into hairpin loop structures. These hairpin loops contain most of the cis-acting information required for DNA replication and packaging and act as hinges during replication to change the direction of replication. When the genome is converted to double-stranded forms, replication origin sites are created involving sequences in and adjacent to the hairpins.
Structure
thumb|250 px|Schematic diagram of a Parvoviridae [[virion]]
thumb|250 px|A diagram of the canine parvovirus's capsid, containing 60 monomers of the capsid protein.
Parvovirus virions are 23–28 nanometers (nm) in diameter and consist of the genome enclosed inside a capsid that is icosahedral in shape with a rugged surface. The capsid is composed of 60 structurally equivalent polypeptide chains derived from the C-terminal end of a VP protein's sequence, interlocking extensively to form an icosahedron with 60 asymmetric, superficial triangular units. These units have 3-fold radial symmetry at two vertices and 5-fold radial symmetry at one, with 2-fold radial symmetry at the line opposite of the 5-fold vertex and a 2/5 circular fold wall surrounding the point of the 5-fold vertex. Twenty 3-fold vertices, thirty 2-fold lines, and twelve 5-fold vertices exist per capsid, the latter corresponding to the 12 vertices of the icosahedron. surrounded by canyon-like depressions at the 5-fold axes. Each of these cylinders potentially contains an opening to connect the exterior of the capsid to the interior, which mediates entry and exit of the genome. About 20 nucleotides from the 5′-end of the genome may remain exposed outside of the capsid carrying a copy of NS1 bound to the 5′-end, which is a result of how the genome is synthesized and packaged. Infected cells that enter S-phase are forced to synthesize viral DNA and cannot leave S-phase. Parvoviruses establish replication foci in the nucleus that grow progressively larger as infection progresses.
Once a cell enters S-phase and the genome is uncoated, a host DNA polymerase uses the 3′-end of the 3′ hairpin as a primer to synthesize a complementary DNA strand for the coding portion of the genome, which is connected to the 5′-end of the 5′ hairpin. Messenger RNA (mRNA) that encodes NS1 is then transcribed from the genome by the DNA polymerase, capped and polyadenylated, and translated by host ribosomes to synthesize NS1. In contrast to these other replication initiator proteins, NS1 shows only vestigial traces of being able to perform ligation, which is a key part of rolling circle replication. The Bidnaviridae family, which are also linear ssDNA viruses, appear to be descended from a parvovirus that had its genome integrated into the genome of a polinton, a type of DNA transposon related to viruses in the realm Varidnaviria. Parvoviruses in the Hamaparvovirinae lineage are likely all heterotelomeric, Densovirinae are exclusively homotelomeric, and Parvovirinae varies.
- Densovirinae
::Aquambidensovirus
::Blattambidensovirus
::Diciambidensovirus
::Hemiambidensovirus
::Iteradensovirus
::Miniambidensovirus
::Muscodensovirus
::Pefuambidensovirus
::Protoambidensovirus
::Scindoambidensovirus
::Tetuambidensovirus
- Hamavirinae
::Chaphamavirus
::Coluhamavirus
::Embehamavirus
::Ichthamavirus
- Hepanvirinae
::Protohepanvirus
- Metallovirinae
::Protometallovirus
- Parvovirinae
::Amdoparvovirus
::Artiparvovirus
::Aveparvovirus
::Bocaparvovirus
::Copiparvovirus
::Dependoparvovirus
::Erythroparvovirus
::Loriparvovirus
::Protoparvovirus
::Sandeparvovirus
::Tetraparvovirus
- Penbrevirinae
::Brevipenbrevirus
::Shripenbrevirus
Disease
thumb|164x164px|Child with Fifth disease
In humans, the most prominent parvoviruses that cause disease are parvovirus B19 and human bocavirus 1. B19 infection is often asymptomatic but can manifest in a variety of ways, including Fifth disease with its characteristic rash in children, persistent anemia in immunocompromised persons and in people who have underlying hemoglobinopathies, transient aplastic crises, hydrops fetalis in pregnant women, and arthropathy. Human bocavirus 1 is a common cause of acute respiratory tract infection, especially in young children, wheezing being a common symptom. Other parvoviruses associated with different diseases in humans include human parvovirus 4 and human bufavirus, though the manner by which these viruses cause disease is unclear. Feline parvovirus, a closely related virus, likewise causes severe illness in cats along with panleukopenia. In pigs, porcine parvovirus is a major cause of infertility as infection frequently leads to death of the fetus.
Use in medicine
Adeno-associated viruses have become an important vector for gene therapy aimed at treating genetic diseases, such as those caused by a single mutation. The recombinant AAV (rAAV) contains a viral capsid but lacks a complete viral genome. Instead, the typical nucleic acid packaged into the capsid contains a promoter region, the gene of interest, and a terminator region, all contained within two inverted terminal repeats derived from the viral genome. rAAV essentially acts as a container that can traverse the cell membrane and deliver its nucleic acid cargo to the nucleus.
History
Parvoviruses were discovered relatively late in comparison to other prominent virus families, potentially due to their small size. In the late 1950s and 1960s, a variety of animal parvoviruses were discovered, including minute virus of mice, which has since been used extensively to study rolling hairpin replication. Many AAVs were also discovered during this time period and research on them led to their first usage in gene therapy in the 1980s. Over time, improvements in aspects such as vector design led to certain AAV gene therapy products reaching clinical efficacy in 2008 and being approved in the following years. B19 was later recognized as a species by the International Committee on Taxonomy of Viruses (ICTV) in 1985, and throughout the 1980s it increasingly became associated with various diseases. The family was reorganized in 2019, departing from the "traditional" invertebrate-vertebrate distinction between Densovirinae and Parvovirinae and instead distinguishing the subfamilies based on helicase phylogeny, leading to the establishment of a new subfamily, Hamaparvovirinae. The order Piccovirales takes the first part of its name from the Italian word piccolo, meaning small, and the second part is the suffix used for virus orders. The class Quintoviricetes takes the first part of its name from the Galician word quinto, meaning fifth, referring to fifth disease (erythema infectiosum) caused by parvovirus B19, and viricetes, the suffix used for virus classes.