Human bocavirus

Human bocavirus (HBoV) is a parvovirus that has been suggested to cause human disease. It is a probable cause of lower respiratory tract infections and it has been linked to gastroenteritis, although the role of this emerging infectious disease in human disease has not been firmly established. The term human bocavirus can refer to any bocaparvovirus strain in the Primate bocaparvovirus 1 and Primate bocaparvovirus 2 species that infects humans.

<h2>History

Allander and colleagues at the Karolinska Institutet in Stockholm, Sweden, first cloned this new member of the family of Parvoviridae in 2005 from pooled nasopharyngeal aspirates (NPA, collection of aspirated fluid from the back of the nasal cavity). They used a novel technique called molecular virus screening, based on random cloning and bioinformatical analysis. This technique has led to the discovery of new viruses such as polyomavirus KI (Karolinska Institute) and WU (Washington University), which are closely related to each other and have been isolated from respiratory secretions.

Several groups of scientists have since then found that HBoV is the fourth most common virus in respiratory samples, behind respiratory syncytial virus, adenoviruses (155, 28%) and rhinoviruses.

The name bocavirus is derived from bovine and canine, referring to the two known hosts for other members of this genus; the bovine parvovirus which infects cattle, and the minute virus of canines which infects dogs. Parvoviruses (Latin: small viruses) have a 5 kilobase long single-stranded DNA, and they use some of their host's replication proteins to copy their DNA.

Virology

The virons are small (diameter 18-26 nanometers), icosahedral and non enveloped. The capsid has a T = 1 symmetry and consists of 60 copies of coat protein. The coat proteins have a conserved, eight stranded beta barrel motif that forms the core of the capsid. There is also a conserved alpha helix.

The HBoV capsid shares three characteristic features also found in the other vertebrate parvoviruses: (1) a dimple like depression at each icosahedral 2-fold axis; (2) a large trimeric protrusion surrounds each 3-fold axis or is located at the 3-fold axis; (3) a channel at each 5-fold axis whose outermost opening is formed by a small pentameric structure encircled by a wide canyon like region. While this dimple is also found among the invertebrate parvoviruses they lack the 3-fold protrusions and canyon around the 5-fold channel. The external diameter of the capsid ranges from ∼21.5 nanometers (nm) at the lowest points of the dimple and canyon to ∼28 nm at the top of the protrusion.

The genome is a linear, single-stranded DNA 5.2-5.3 kilobases in length with terminal hairpin structures at both ends.

The genome encodes 3 open reading frames (ORF1, 2 and 3). The two left most ORFs encode 2 non structural proteins (NS1 and NP1). The right hand ORF (ORF3) encodes the capsid proteins (VP1 and VP2). The NP1 gene is in an alternate reading frame to VP1 and overlaps the start of VP1 by 13 nucleotides. Similarly, VP2 is collinear to VP1 and results from initiation of translation at a downstream ATG and co-terminates.

NP1 is a small non-structural protein that could induce apoptosis in transfection of HeLa cells.

There is a single promoter located within the 3' hairpin. This is responsible for, by alternative splicing and alternative polyadenylation, for the generation of several (at least 6) mRNAs. The poly A tail is ~150 nucleotides in length.

After nuclear import the single stranded genome is converted to double stranded DNA and production of the viral NS1 protein commences.

The genome is replicated through a unique rolling hairpin mechanism that is dependent on the NS1 protein. Replication results in the creation of a series of circular head to tail sequences.

A sequence conserved among the Parvoviridae TAAAAAT is found close to the 3' terminus.

Other parvoviruses replicate only when the host cell is in S phase: viral replication results in the death of the host cell. This pattern has not yet been experimentally confirmed for the bocaviruses but seems likely to be the case. Expression of the viral proteins alone does not cause host cell death. unlike other parvoviruses where this has been examined.

The receptor for bovine parvovirus 1 is sialic acid.

Molecular biology

NS1 belongs to the superfamily III (SF3) helicases all of which travel along DNA in a 3′-to-5′ direction. Four conserved sequence motifs in are found in SF3 helicases (A, B, B′, and C). These motifs form the nucleoside triphosphate binding pocket, the metal ion coordination site, the DNA-binding site and the sensory element. These motifs are in a stretch of approximately 100 amino acid residues in the middle of NS1. These helicases surround DNA as a ring of six or eight subunits with the ATP binding pocket lying between adjacent subunits. The first subunit provides the A and B motifs, and the arginine residue of the second subunit functions as a trans-acting arginine finger sensor for ATP binding and hydrolysis status. The arginine finger lies after the C motif but in three dimensions it is often embedded in a cluster of positively charged amino acids. In a ring configuration this domain interacts with the ATP binding pocket of the neighboring subunit.

NS1 binds to both the left and right hand origins of replication on the right with the host's own high mobility group proteins and on the left with glucocorticoid modulatory element-binding proteins. Origin recognition leads to strand- and site-specific nicking of viral DNA, processes that require ATP for tight binding and subsequent nicking. The NS1 protein remains covalently linked to the 5′ end of nicked DNA with the 3′-hydroxyl group being used for synthesis of the nascent strand. Replication of the genome is thought to be mediated by DNA polymerase δ. This polymerase is usually involved in repair of DNA after the excision of nucleotides. This process involves proliferating cell nuclear antigen, the single strand-binding protein replication protein A and NS1. In this process NS1 acts as an ATP powered helicase to resolve terminal hairpin structures of the viral genome.

In addition to these functions NS1 enhances transcription from a viral capsid promoter, may assist in packing DNA into newly formed capsids and is responsible for the cytopathic effect of parvoviruses.

Genetics

There is 78%, 67%, and 80% identity between Human Bocavirus 1 and 2 NS1, NP1, and VP1/VP2 proteins respectively.

There are four known human genotypes of this virus: type 1 to 4. Types 1 and 2 appear to have diverged recently (circa 1985) Recombination may occur between strains. The estimated mean evolutionary rate is 8.6 x 10(-4) substitutions/site/year. The 1st + 2nd codon positions evolve 15 times more slowly than those of the 3rd codon position.

Phylogenetic analysis of this genus groups the swine bocavirus with canine minute virus.

Bocaviruses have been isolated from pigs

Human bocavirus 3 appears to be a recombinant of human bocavirus 1 and human bocavirus 2 and 4.

Incomplete sequences of bocaviruses have been obtained from wild chimpanzees. These sequences phlyogenetically lie within the known human bocavirus isolates but also show evidence of recombination.

Clinical

HBoV is found in respiratory samples from healthy subjects. In patients with respiratory complaints, it can be found alone or, more often, in combination with other viruses known to cause respiratory complaints. Newborns are probably protected by passive immunisation. The age group most frequently affected appear to be children between the ages of six months to two years, although cases in children older than five and even in a 28-year-old have been reported.

HBoV can be detected not only in respiratory samples but also in blood, urine, and stools. The latter two may merely reflect viral shedding, although diarrhoea has been described in animal bocaviral infections, and some patients with HBoV seem to have diarrhoea independent of respiratory symptoms.

A study in Jordan found that 9% of 220 children hospitalised with lower respiratory tract infection were infected with bocavirus. Of those infected the median age was 4 months. Coughing (100%), wheezing (82.7%) and fever (68.2%) were the most common clinical findings with bronchopneumonia (35%) and bronchiolitis (30%) being the most common ultimate diagnoses.

HBoV1 has been generally associated with respiratory symptoms while other HBoV tend to be associated with diarrhea and acute flaccid paralysis.

Although most cases are mild severe respiratory disease has also been reported.

Life-threatening infection caused by human bocavirus was described in previously healthy 20-months old prematurely born child.

References

External links

• Allander T (January 2008). "Human bocavirus". J. Clin. Virol. 41 (1): 29â€"33. doi:10.1016/j.jcv.2007.10.026. PMID 18055252. 
• ViralZone: Bocavirus