Human Parvoviruses

Abstract

Parvovirus B19 (B19V) and human bocavirus 1 (HBoV1), members of the large Parvoviridae family, are human pathogens responsible for a variety of diseases. For B19V in particular, host features determine disease manifestations. These viruses are prevalent worldwide and are culturable in vitro, and serological and molecular assays are available but require careful interpretation of results. Additional human parvoviruses, including HBoV2 to -4, human parvovirus 4 (PARV4), and human bufavirus (BuV) are also reviewed. The full spectrum of parvovirus disease in humans has yet to be established. Candidate recombinant B19V vaccines have been developed but may not be commercially feasible. We review relevant features of the molecular and cellular biology of these viruses, and the human immune response that they elicit, which have allowed a deep understanding of pathophysiology.

Keywords: B19 virus; human bocavirus; parvovirus.

FIG 1

B19V transcription map. (A) B19V packages a linear ssDNA genome of either positive or negative polarity. The ssDNA genome of B19V is shown in negative polarity. Two ITRs (nt 1 to 383 and nt 5214 to 5596) are diagrammed at two ends of the genome with unpaired or mismatched bases in the palindromes represented by “bulges” or “bubbles,” respectively. (B) Schematic diagram of the duplex replicative form (RF) of the B19V genome. It is capable of expressing viral genes, replicating, and producing progeny virions. The P6 promoter, the RNA initiation site, splice donor sites (D1 and D2), splice acceptor sites (A1-1, A1-2, A2-1, and A2-2), and proximal/distal polyadenylation sites [(pA)p/(pA)d] are indicated, along with the nine major mRNAs (R1 to R9) that are polyadenylated at nt 2840 of the major (pA)p site and three minor mRNAs (R1′ to R3′) that are polyadenylated at nt 3141 of the minor (pA)p site. The numbering of nucleotides is according to the numbering for the B19V J35 isolate (GenBank accession no. AY386330). Proteins encoded by each mRNA are shown on the right with detected molecular masses in kilodaltons. The ITRs and the NS1- and VP1-encoding regions are not to scale. The coding capabilities of R3 and R3′ mRNAs are unknown. The size of each mRNA is shown in nucleotides without inclusion of the poly(A) tail. Different ORFs are depicted in different-colored boxes.

FIG 2

B19V infection of human erythroid progenitor cells (B19V life cycle). When human erythroid progenitor cells are infected with B19V, the virus initially interacts with P antigen (globoside) (step 1), the primary low-affinity attachment sugar molecule on the cell surface. This interaction confers a conformational change of VP1, extruding itself on the surface of the virion instead of remaining embedded inside the virion (step 2). The VP1u region on the virion then binds a putative cellular surface receptor (VP1u-interacting protein), which mediates internalization of the virion inside the cells, presumably by endocytosis (step 3). Virions undergo several steps of intracellular trafficking in the endosome, are eventually released from the endosome through a function of the PLA2 motif of VP1u, and enter the nucleus (step 4). In the nucleus, the virion is uncoated and releases either a positive-sense ssDNA or a negative-sense ssDNA (−ssDNA) genome (step 5). The ssDNA genome, shown as negative-sense ssDNA, is first converted into dsDNA that is primed by the 3′ OH of the left-hand ITR (step 6), a process that requires cellular DNA polymerase (DNA Pol) and other DNA replication factors. Phosphorylated STAT5 (p-STAT5), which is activated through the Epo/Epo-R/Jak2/STAT5 pathway, is required for viral DNA replication. After dsDNA conversion, NS1 binds NSBEs and nicks one of the strands at the trs (step 7a). This event creates a new 3′ OH to lead DNA synthesis following melting of the hairpinned ITR, which subsequently repairs the ITR and results in an open-ended duplex replicative intermediate (step 7b). The repaired ITR is then denatured (step 7c), which likely requires the helicase activity of NS1, and is reannealed, in a process termed reinitiation, to form a double-hairpinned intermediate, which creates a new 3′ primer (3′ OH) to initiate a round of strand displacement synthesis (step 7d). The RF DNA is capable of transcription of viral mRNA by cellular RNA polymerase II (RNA Pol II). Various B19V mRNAs are generated through alternative processing of the pre-mRNA (step 9) and are exported to the cytoplasm (step 10). Capsid proteins; VP1 and VP2; and the NS1, 11-kDa, and 7.5-kDa nonstructural proteins are translated in the cytoplasm (step 11). VP1 and VP2 are assembled as trimers (capsid precursors), which are transported into the nucleus (step 12a) to assemble empty capsids (step 13). A viral ssDNA genome is presumably produced through a process called strand displacement (step 7e), when an empty capsid is available, through a putative NS1-mediated packaging mechanism (step 14). NS1 is transported to the nucleus (step 12b) and is essential for viral DNA replication. NS1 also induces cell cycle arrest at G₂ phase. Finally, apoptosis is induced, in which both NS1 and the 11-kDa protein play important roles (step 16). Apoptosis releases the matured virion from infected cells through the broken nuclear membrane (step 15). As noted, steps 6, 7, and 12 to 14 are partially hypothetical.

FIG 3

HBoV1 transcription map. The ssDNA genome of HBoV1 is shown in negative polarity. The transcription and posttranscriptional units are depicted to scale, including the P5 promoter, 5′ splice donor sites (D1, D1′, D2, and D3), 3′ splice acceptor sites (A1, A1′, A2, and A3), the internal proximal polyadenylation site [(pA)p], and the distal polyadenylation site [(pA)d], which are functional when the ssDNA genome is converted to a dsDNA form. The left- and right-end hairpin structures of the genome (LEH and REH, respectively) are diagrammed. Six groups of HBoV1 mRNA transcripts detected during infection, which have either a long form of mRNA (Rx_L) that reads through the (pA)p site or a short form of mRNA (Rx_S) that is polyadenylated at the (pA)p site, are shown below the diagrammed genome. R1 mRNA has a minor species (R1m) that is unspliced at the central small intron (D3-A3). Major ORFs are depicted as colored boxes with the nucleotide and amino acid of the start codon and the stop codon indicated. Proteins expressed from each mRNA species are indicated beside their respective mRNAs with molecular masses in kilodaltons detected during infection.

FIG 4

Transcription map of PARV4. The incomplete PARV4 ssDNA genome (GenBank accession no. NC_007018) is shown to scale in negative sense with predicted inverted terminal repeats (ITRs). Transcription units, including promoters, the polyadenylation site [poly(A)], and splice donor (D) and acceptor (A) sites, are indicated with their respective nucleotide positions. Major detected mRNA species are diagrammed to display their identities and respective sizes in the absence of the poly(A) tail. The encoding ORFs are diagrammed in colored boxes, and the predicted molecular masses (kilodaltons) of translated proteins and detected molecular masses upon transfection are indicated at the right. Potential VP1 start sites are speculated to be located at nt 2378 for a VP1 protein of 914 aa and at nt 2678 for a VP1 protein of 814 aa, as shown. ND, not detected.