Parvovirus Replication

Parvoviruses are very small (between 18 and 25 nm in diameter), non-enveloped, single-stranded DNA viruses with an icosahedral capsid. DNA replication of these viruses occurs in the nucleus, and some general replication strategies are employed; for example, the virus needs to make mRNAs that can be translated into proteins and it needs to replicate the genome using enzymes from the cell.

Cell infection by parvoviruses reveals many of the features seen for other viruses which replicate in the nucleus, but the small and stable parvovirus particles must undergo more subtle changes during the various steps of the process. Furthermore, different species of parvoviruses can exhibit certain specificities during replication cycle.

Replication process

Before the start of any replication, parvoviruses must first enter the cell. An attachment to host receptors initiates clathrin-mediated endocytosis of the virion into the host cell. The virion consequently penetrates into the cytoplasm via permeabilization of host endosomal membrane, and reaches the nucleus (where uncoating occurs) via microtubular transport.

In order to replicate their genetic material, viruses have to recruit and assemble replication factors at an origin of replication. The non-structural replication proteins (NS and Rep) of the parvoviruses represent fundamental viral proteins that recognize the replication origins within the terminal repeats.

Since the parvoviral genome is a single-stranded DNA, no special polymerases are necessary for replication, thus even naked viral nucleic acid is infectious. This single copy of DNA is initially converted to a duplex replication intermediate by cellular proteins.

Transcription of newly formed double-stranded DNA gives rise to viral mRNAs when host cell enters S-phase (or synthesis phase) of the cell cycle and are subsequently translated to produce viral proteins. It generates an ensemble of mature transcripts, as a result of both co and posttranscriptional events.

Replication proceeds through cycles of terminal resolution and hairpin-primed strand displacement synthesis via a rolling hairpin mechanism. During this process, individual genomes are excised and their telomeres regenerated by the introduction of single-strand nicks into replication origins generated at either end of each genome.

Newly synthesized single-stranded DNA can either be converted to double-stranded DNA and serve once again as a template for transcription or replication, or it can be encapsidated to form new virions that are released by cell lysis. It must be noted that Parvoviridae can replicate autonomously only in actively cycling cells; otherwise, co-infection with other viruses (such as adenovirus or herpesvirus) is essential.

Specificities of human parvovirus B19 replication

The human parvovirus B19 virus can replicate only in human erythroid progenitor cells, and for cell binding and subsequent infection the erythrocyte P antigen (globoside) is required. Still, a myriad of cells which also express globoside on their surfaces are not susceptible to infection, partly due to an intracellular blocking of the viral message transcription in nonerythroid cells, but also because specific co-receptors are lacking.

Therefore co-receptors (identified as α5β1 integrins) are needed for binding and internalization of parvovirus B19 particles. These integrins function as receptors for the extracellular matrix component fibronectin, with ligand-induced activation involved in numerous cellular functions that include attaching, trafficking, proliferation and differentiation.

Replicative intermediates of human parvovirus B19 have not been thoroughly characterized. Single-stranded DNA, monomeric double-stranded DNA, and dimeric double-stranded DNA forms can all be detected in productively infected cells. The role of the NS1 protein in parvovirus B19 replication was also investigated, but the exact benefits of host cell cycle arrest for this virus remain elusive.