Parvoviridae

The Parvoviridae are a family of small, rugged, genetically-compact DNA viruses, known collectively as parvoviruses. There are currently >75 species in the family, divided among 13 genera and two subfamilies. Members of this family infect a wide array of animal hosts and have been divided into two subfamilies, which infect either vertebrates (the Parvovirinae) or invertebrates (Densovirinae). Parvovirus B19 was the first pathogenic human parvovirus to be discovered and is best known for causing a childhood exanthem called 'fifth disease' (erythema infectiosum), although it is also associated with other diseases including arthritis. Canine parvovirus causes a virulent and contagious disease in dogs. In cats, a parvovirus causes feline distemper. Parvovirus particles (virions) have a durable non-enveloped protein capsid ~20–30 nm in diameter that contains a single copy of the linear single-stranded ~ 5kb DNA genome, which terminates in small imperfect palindromes that fold into dynamic hairpin telomeres. These terminal hairpins are hallmarks of the family, giving rise to the viral origins of DNA replication and mediating multiple steps in the viral life cycle including genome amplification, packaging, and the establishment of transcription complexes. However, they are often refractory to detection by PCR amplification strategies since they tend to induce polymerase strand-switching. Many parvoviruses are exceptionally resistant to inactivation, remaining infectious for months or years after release into the environment. Viruses in this family have small protein virions that exhibit T=1 icosahedral symmetry. Their capsid shells are assembled from 60 icosahedrally-ordered copies of a single core protein (VP) sequence, but some of these VP proteins also have N-terminal extensions that are not visible in X-ray structures. Biochemical and serological studies indicate that these extensions become successively exposed at the particle surface during virus maturation and cell entry, where they contribute to virion stability and mediate specific steps in cell trafficking. Parvoviruses appear to be unique in encoding a broad spectrum phospholipase A2 (PLA2) activity, typically in the N-terminus of the longest (VP1) subset of their capsid proteins, which is deployed to mediate virion transfer across the lipid bilayer of host cells The viral genome is 4–6 kilobases in length and terminates in imperfectly-palindromic hairpin sequences of ~120–500 nucleotides that exhibit genus-specific secondary structures, and can either be identical at the two ends of the genome (homotelomeric) or can differ in size, sequence and predicted secondary structure (heterotelomeric). Homotelomeric viruses package DNA strands of both senses (into separate capsids) whereas heterotelomeric viruses generally package predominantly negative-sense DNA (discussed in references 6 and 7). All parvoviruses encode two major gene complexes: the non-structural (or rep) gene that encodes the replication initiator protein (called NS1 or Rep), and the VP (or cap) gene, which encodes a nested set of ~2–6 size variants derived from the C-terminus of the single VP protein sequence. Members of the Parvovirinae also encode a few (1–4) small genus-specific ancillary proteins that are variably distributed throughout the genome, show little sequence homology to each other, and appear to serve an array of different functions in each genus (references 3–7). Viruses in most genera are mono-sense, meaning that both viral genes are transcribed in a single direction from open reading frames in the same (positive-sense) DNA strand, but members of one genus of homotelomeric invertebrate viruses (genus Ambidensovirus) show ambisense organization, with the NS and capsid proteins being transcribed in opposite directions from the 5’-ends of the two complementary DNA strands (see reference 1 and ). The major non-structural protein, NS1, is a site- and strand-specific endonuclease belonging to the HuH protein superfamily, and also carries a AAA+ SF3 helicase domain. NS1 initiates and drives the viral “rolling hairpin” replication mechanism (RHR), which is a linear adaptation of the more-common “rolling-circle” replication strategy used by many small circular prokaryotic and viral replicons. RHR is a unidirectional mechanism that displaces a single, continuous DNA strand, which rapidly folds and refolds to generate a series of concatemeric duplex replication intermediates. Unit length genomes are then excised from these intermediates by the NS1 endonuclease (reviewed in references 5 and 6), and packaged 3’-to-5’ into preformed empty capsids driven by the SF3 helicase activity of NS1/Rep. Viral replication is nuclear. Entry into the host cell is achieved by attachment to host receptors, which mediate internalization via endocytosis. Capsids are metastable, undergoing a series of structural shifts during cell entry that sequentially expose peptides carrying PLA2 activity and trafficking signals . These signals ultimately mediate delivery of the intact virion into the cell nucleus, where genome uncoating allows the establishment of viral DNA replication and transcription complexes that rely predominantly upon the synthetic machinery of their host cell. Replication follows the unidirectional strand displacement mechanism discussed above. Packaged virions from viruses in at least two genera (Protoparvovirus and Bocaparvovirus) have mechanisms that allow mature virions to be trafficked out of viable host cells prior to cell lysis, but members of most other genera are only released into the environment following death and lysis of the infected cell. Natural animal hosts for parvoviruses include a wide range of vertebrates, arthropods (insects and some crustacea) and echinoderms (sea stars). For viruses in the Parvovirinae transmission routes are commonly fecal-oral or respiratory.