Editing Parvoviridae (section)

==Life cycle==
Parvoviruses enter cells by [[endocytosis]], using a variety of cellular receptors to bind to the host cell. In [[endosome]]s, many parvoviruses undergo a change in conformation so that the [[phospholipase]] A2 (PLA{{sub|2}}) domain on the VP1 N-termini are exposed so the virion can penetrate lipid bilayer membranes. Intracellular trafficking of virions varies, but virions ultimately arrive to the nucleus, inside of which the genome is uncoated from the capsid. Based on studies of minute virus of mice (MVM), the genome is ejected from the capsid in a 3′-to-5′ direction from one of the openings in the capsid, leaving the 5′-end of the DNA attached to the capsid.<ref name=cotmoreictv />

Parvoviruses lack the ability to induce cells into their [[DNA replication]] stage, called S-phase, so they must wait in the nucleus until the host cell enters S-phase on its own. This makes cell populations that divide rapidly, such as fetal cells, an excellent environment for parvoviruses. Adeno-associated viruses (AAV) are dependent on helper viruses, which may be an [[adenovirus]] or a [[herpesvirus]], since coinfection alters the cellular environment to allow for replication.<ref name=cotmoreictv /> In the absence of coinfection, AAV's genome is integrated into the host cell's genome until coinfection occurs.<ref name=cotmore1996 >{{cite journal |vauthors=Cotmore SF, Tattersall P |year=1996 |title=Parvovirus DNA replication |url=http://www.hixonparvo.info/Peter%20Parvo%20DNA%20replication%20Review%201996.pdf |journal=Cold Spring Harbor Monograph Archive |volume=31 |pages=799–813 |doi=10.1101/0.799-813 |doi-broken-date=1 November 2024 |access-date=24 January 2021 |archive-date=17 October 2021 |archive-url=https://web.archive.org/web/20211017102605/http://www.hixonparvo.info/Peter%20Parvo%20DNA%20replication%20Review%201996.pdf |url-status=dead }}</ref> 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.{{sfn|Kerr|Cotmore|Bloom|2005|p=175}}

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 [[Ligation (molecular biology)|connected]] to the 5′-end of the 5′ hairpin.{{sfn|Kerr|Cotmore|Bloom|2005|p=177}}<ref name=cotmore1996 /><ref name=martin >{{cite journal |vauthors=Martin DP, Biagini P, Lefeuvre P, Golden M, Roumagnec P, Varsani A |date=September 2011 |title=Recombination in eukaryotic single stranded DNA viruses |journal= Viruses|volume=3 |issue=9 |pages=1699–1738 |doi=10.3390/v3091699 |pmc=3187698 |pmid=21994803|doi-access=free }}</ref> [[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.<ref name=cotmoreictv /><ref name=cotmore2013 />{{sfn|Kerr|Cotmore|Bloom|2005|p=173}} If proteins are encoded in multiple co-linear frames, then alternative splicing, suboptimal translation initiation, or [[leaky scanning]] may be used to translate different gene products.<ref name=cotmoreictv />

Parvoviruses replicate their genome via [[rolling hairpin replication]], a unidirectional, strand displacement form of DNA replication that is initiated by NS1. Replication begins once NS1 binds to and makes a nick in a replication origin site in the duplex DNA molecule at the end of one hairpin. Nicking releases the 3′-end of the nicked strand as a free [[hydroxyl]] (-OH) to prime DNA synthesis<ref name=cotmoreictv /> with NS1 remaining attached to the 5′-end.<ref name=cotmore1996 /> The nick causes the adjacent hairpin to unfold into a linear, extended form. At the 3′-OH, a replication fork is established using NS1's helicase activity, and the extended telomere is replicated by the DNA polymerase.{{sfn|Kerr|Cotmore|Bloom|2005|p=173}}{{sfn|Kerr|Cotmore|Bloom|2005|p=180}} The two telomere strands then refold back in on themselves to their original configurations, which repositions the replication fork to switch templates to the other strand and move in the opposite direction toward the other end of the genome.{{sfn|Kerr|Cotmore|Bloom|2005|p=179}}{{sfn|Kerr|Cotmore|Bloom|2005|p=181}}

Parvoviruses vary in whether the termini are similar or the same, called homotelomeric parvoviruses, or different, called heterotelomeric parvoviruses. In general, homotelomeric parvoviruses, such as AAV and B19, replicate both ends of their genome through the aforementioned process, called terminal resolution, and their hairpin sequences are contained within larger (inverted) terminal repeats. Heterotelomeric viruses, such as minute virus of mice (MVM), replicate one end by terminal resolution and the other end via an asymmetric process called junction resolution<ref name=cotmoreictv />{{sfn|Kerr|Cotmore|Bloom|2005|p=171–172, 177, 179}} so that the correct orientation of the telomere can be copied.{{sfn|Kerr|Cotmore|Bloom|2005|p=182}}

During asymmetric junction resolution, the duplex extended-form telomeres refold in on themselves into a cruciform shape. A replication origin site on the lower strand of the right arm of the cruciform is nicked by NS1, leading to the lower arm of the cruciform unfolding into its linear extended form. A replication fork established at the nick site moves down the extended lower arm to copy the lower arm's sequence. The two strands of the lower arm then refold to reposition the replication fork to go back toward the other end, displacing the upper strand in the process.{{sfn|Kerr|Cotmore|Bloom|2005|p=182–184}}

The back and forth, end-to-end pattern of rolling hairpin replication produces a concatemer containing multiple copies of the genome.<ref name=cotmoreictv />{{sfn|Kerr|Cotmore|Bloom|2005|p=177}} NS1 periodically makes nicks in this molecule and, through a combination of terminal resolution and junction resolution, individual strands of the genome are excised from the concatemer.<ref name=martin />{{sfn|Kerr|Cotmore|Bloom|2005|p=181}} Excised genomes may either be recycled for further rounds of replication or packaged into progeny capsids.<ref name=cotmore1996 /> Translation of mRNA containing VP proteins leads to the accumulation of capsid proteins in the nucleus that assemble into these empty capsids.{{sfn|Kerr|Cotmore|Bloom|2005|p=175}}

Genomes are encapsidated at one of the capsid's vertices through a portal,<ref name=cotmoreictv /> potentially the one opposite the portal used to expel the genome.<ref name=cotmore2013 /> Once complete virions have been constructed, they may be exported from the nucleus to the exterior of the cell before disintegration of the nucleus. Disruption of the host cell environment may also occur later on in the infection. This results in cell [[lysis]] via [[necrosis]] or [[apoptosis]], which releases virions to the outside of the cell.<ref name=cotmoreictv />{{sfn|Kerr|Cotmore|Bloom|2005|p=175}}