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** ''[[Alphapapillomavirus]]''
** ''[[Betapapillomavirus]]''
** ''[[
** ''[[Deltapapillomavirus]]''
** ''[[
** ''[[Zetapapillomavirus]]''▼
** ''[[Etapapillomavirus]]''
** ''[[Thetapapillomavirus]]''▼
** ''[[Iotapapillomavirus]]''▼
** ''[[Kappapapillomavirus]]''▼
** ''[[Lambdapapillomavirus]]''▼
** ''[[Mupapillomavirus]]''▼
** ''[[Nupapillomavirus]]''▼
** ''[[Xipapillomavirus]]''▼
** ''[[Omikronpapillomavirus]]''▼
** ''[[Pipapillomavirus]]''▼
** ''[[Rhopapillomavirus]]''▼
** ''[[Sigmapapillomavirus]]''▼
** ''[[Taupapillomavirus]]''▼
** ''[[Upsilonpapillomavirus]]''▼
** ''[[Phipapillomavirus]]''▼
** ''[[Chipapillomavirus]]''
** ''[[Psipapillomavirus]]''▼
** ''[[Omegapapillomavirus]]''▼
** ''[[Dyodeltapapillomavirus]]''
** ''[[Dyoepsilonpapillomavirus]]''
** ''[[Dyozetapapillomavirus]]''
** ''[[Dyoetapapillomavirus]]''
** ''[[Dyothetapapillomavirus]]''▼
** ''[[Dyoiotapapillomavirus]]''
** ''[[Dyokappapapillomavirus]]''
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** ''[[Dyomupapillomavirus]]''
** ''[[Dyonupapillomavirus]]''
** ''[[
** ''[[Dyoomikronpapillomavirus]]''
** ''[[Dyopipapillomavirus]]''
** ''[[Dyorhopapillomavirus]]''
** ''[[Dyosigmapapillomavirus]]''
** ''[[Dyotaupapillomavirus]]''
▲** ''[[Dyothetapapillomavirus]]''
** ''[[Dyoupsilonpapillomavirus]]''
** ''[[
** ''[[
** ''[[
** ''[[
▲** ''[[Iotapapillomavirus]]''
▲** ''[[Kappapapillomavirus]]''
▲** ''[[Lambdapapillomavirus]]''
▲** ''[[Mupapillomavirus]]''
▲** ''[[Nupapillomavirus]]''
▲** ''[[Omegapapillomavirus]]''
▲** ''[[Omikronpapillomavirus]]''
▲** ''[[Phipapillomavirus]]''
▲** ''[[Pipapillomavirus]]''
▲** ''[[Psipapillomavirus]]''
▲** ''[[Rhopapillomavirus]]''
▲** ''[[Sigmapapillomavirus]]''
▲** ''[[Taupapillomavirus]]''
▲** ''[[Thetapapillomavirus]]''
** ''[[Treisdeltapapillomavirus]]''
** ''[[Treisepsilonpapillomavirus]]''
** ''[[Treiszetapapillomavirus]]''▼
** ''[[Treisetapapillomavirus]]''
** ''[[Treisthetapapillomavirus]]''▼
** ''[[Treisiotapapillomavirus]]''
** ''[[Treiskappapapillomavirus]]''
▲** ''[[Treisthetapapillomavirus]]''
▲** ''[[Treiszetapapillomavirus]]''
▲** ''[[Upsilonpapillomavirus]]''
▲** ''[[Xipapillomavirus]]''
▲** ''[[Zetapapillomavirus]]''
* ''[[Secondpapillomavirinae]]''
** ''[[Alefpapillomavirus]]''
}}
'''''Papillomaviridae''''' is a [[Family (biology)|family]] of non-[[viral envelope|enveloped]] [[DNA virus]]es whose members are known as papillomaviruses.<ref>{{cite journal |last1=Van Doorslaer |first1=K |last2=Chen |first2=Z |last3=Bernard |first3=HU |last4=Chan |first4=PKS |last5=DeSalle |first5=R |last6=Dillner |first6=J |last7=Forslund |first7=O |last8=Haga |first8=T |last9=McBride |first9=AA |last10=Villa |first10=LL |last11=Burk |first11=RD |last12=Ictv Report |first12=Consortium |title=ICTV Virus Taxonomy Profile: Papillomaviridae. |journal=The Journal of General Virology |date=August 2018 |volume=99 |issue=8 |pages=989–990 |doi=10.1099/jgv.0.001105 |pmid=29927370|pmc=6171710 }}</ref> Several hundred species of papillomaviruses, traditionally referred to as "types",<ref name="pmid15183049">{{cite journal |vauthors=de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H |title=Classification of papillomaviruses |journal=Virology |volume=324 |issue=1 |pages=17–27 |date=June 2004 |pmid=15183049 |doi=10.1016/j.virol.2004.03.033 |doi-access=free }}</ref> have been identified infecting all carefully inspected mammals,<ref name="pmid15183049" /> but also other [[vertebrate]]s such as birds, snakes, turtles and fish.<ref name="pmid18973915">{{cite journal |vauthors=Herbst LH, Lenz J, Van Doorslaer K, Chen Z, Stacy BA, Wellehan JF, Manire CA, Burk RD |title=Genomic characterization of two novel reptilian papillomaviruses, Chelonia mydas papillomavirus 1 and Caretta caretta papillomavirus 1 |journal=Virology |volume=383 |issue=1 |pages=131–5 |date=January 2009 |pmid=18973915 |doi=10.1016/j.virol.2008.09.022 |doi-access=free }}</ref><ref name="pmid9881444">{{cite journal |vauthors=Drury SE, Gough RE, McArthur S, Jessop M |title=Detection of herpesvirus-like and papillomavirus-like particles associated with diseases of tortoises |journal=The Veterinary Record |volume=143 |issue=23 |pages=639 |date=December 1998 |pmid=9881444 }}</ref><ref name="pmid21910860">{{cite journal |vauthors=Lange CE, Favrot C, Ackermann M, Gull J, Vetsch E, Tobler K |title=Novel snake papillomavirus does not cluster with other non-mammalian papillomaviruses |journal=Virology Journal |volume=8 |pages=436 |date=September 2011 |pmid=21910860 |pmc=3179961 |doi=10.1186/1743-422X-8-436 |doi-access=free }}</ref> Infection by most papillomavirus types, depending on the type, is either asymptomatic (e.g. most Beta-PVs) or causes small benign tumors, known as [[papilloma]]s or [[wart]]s (e.g. human papillomavirus 1, HPV6 or HPV11). Papillomas caused by some types, however, such as human papillomaviruses 16 and 18, carry a risk of [[malignant transformation|becoming cancerous]].<ref name="pmid16949995">{{cite journal |vauthors=Muñoz N, Castellsagué X, de González AB, Gissmann L |title=Chapter 1: HPV in the etiology of human cancer |journal=Vaccine |volume=24 Suppl 3 |issue=3 |pages=S3/1–10 |date=August 2006 |pmid=16949995 |doi=10.1016/j.vaccine.2006.05.115 }}</ref>
Papillomaviruses are usually considered as highly [[host tropism|host-]] and tissue-[[tropism|tropic]], and are thought to rarely be transmitted between species.<ref name="pmid18854037">{{cite journal |vauthors=Mistry N, Wibom C, Evander M |title=Cutaneous and mucosal human papillomaviruses differ in net surface charge, potential impact on tropism |journal=Virology Journal |volume=5 |pages=118 |date=October 2008 |pmid=18854037 |pmc=2571092 |doi=10.1186/1743-422X-5-118 |doi-access=free }}</ref> Papillomaviruses replicate exclusively in the [[Stratum germinativum|basal layer]] of the [[stratified squamous epithelium|body surface tissues]]. All known papillomavirus types infect a particular body surface,<ref name="pmid15183049"/> typically the skin or mucosal epithelium of the genitals, anus, mouth, or airways.<ref name="pmid15753007">{{cite journal |vauthors=Doorbar J |title=The papillomavirus life cycle |journal=Journal of Clinical Virology |volume=32
Papillomaviruses were first identified in the early 20th century, when it was shown that skin [[wart]]s, or [[papilloma]]s, could be transmitted between individuals by a filterable infectious agent. In 1935 [[Francis Peyton Rous]], who had previously demonstrated the existence of a cancer-causing [[rous sarcoma virus|sarcoma virus]] in chickens, went on to show that a papillomavirus could cause skin cancer in infected rabbits. This was the first demonstration that a virus could cause cancer in mammals.
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[[Image:PapillomavirusTree3.png|240px|thumb|right|Selected papillomavirus types]]
There are over 100 species of papillomavirus recognised,<ref name=Kocjan2013>{{cite journal |vauthors=Kocjan BJ, Hosnjak L, Seme K, Poljak M |title=Complete Genome Sequence of a Novel Human Betapapillomavirus, HPV-159 |journal=Genome Announcements |volume=1 |issue=3 |pages=e00298–13 |date=May 2013 |pmid=23723399 |pmc=3668007 |doi=10.1128/genomeA.00298-13 }}</ref> though the [[International Committee on Taxonomy of Viruses|ICTV]] officially recognizes a smaller number, categorized into 53 genera, as of 2019.<ref name=ICTV_2018b>{{cite web|url= https://
Phylogenetic studies strongly suggest that PVs normally evolve together with their mammalian and bird host species, but [[adaptive radiation]]s, occasional [[zoonosis|zoonotic events]] and [[genetic recombination|recombinations]] may also impact their diversification.<ref name="MultForce" /> Their basic genomic organization appears maintained for a period exceeding 100 million years, and these sequence comparisons have laid the foundation for a PV taxonomy, which is now officially recognized by the [[International Committee on Taxonomy of Viruses]]. All PVs form the family ''Papillomaviridae'', which is distinct from the ''[[Polyomaviridae]]'' thus eliminating the term ''[[Papovaviridae]]''. Major branches of the phylogenetic tree of PVs are considered [[genus|genera]], which are identified by Greek letters. Minor branches are considered [[species]] and unite PV types that are genomically distinct without exhibiting known biological differences. This new taxonomic system does not affect the traditional identification and characterization of PV "types" and their independent isolates with minor genomic differences, referred to as "subtypes" and "variants", all of which are [[taxon|taxa]] below the level of "species".<ref name=Campo>{{cite book |editor=Campo MS |editor-link=Saveria Campo |title=Papillomavirus Research: From Natural History To Vaccines and Beyond |publisher=Caister Academic Press |year=2006 |url= http://www.horizonpress.com/pv |id=[http://www.horizonpress.com/pv ] |isbn=978-1-904455-04-2}}</ref> Additionally, phylogenetic groupings at higher taxonomic level have been proposed.<ref name="ClinImp">{{cite journal |vauthors=Bravo IG, de Sanjosé Llongueras S, Gottschling M |title=The clinical importance of knowledge about papillomavirus evolution |journal=Trends in Microbiology |year=2010 |volume=18 |issue=10 |pages=432–8 |doi=10.1016/j.tim.2010.07.008 |pmid=20739182 }}</ref>
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==Human papillomaviruses==
{{
Over 170 human papillomavirus types have been completely sequenced.<ref name=Chouhy2013>{{cite journal |vauthors=Chouhy D, Bolatti EM, Pérez GR, Giri AA |title=Analysis of the genetic diversity and phylogenetic relationships of putative human papillomavirus types |journal=The Journal of General Virology |volume=94 |issue=Pt 11 |pages=2480–8 |date=November 2013 |pmid=23997181 |doi=10.1099/vir.0.055137-0 |hdl=2133/9862 |doi-access=free |hdl-access=free }}</ref> They have been divided into 5 genera: Alphapapillomavirus, Betapapillomavirus, Gammapapillomavirus, Mupapillomavirus and Nupapillomavirus. At least 200 additional viruses have been identified that await sequencing and classification.{{
==Animal papillomaviruses==
[[Image:Viral papilloma 1.JPG|thumb|Viral papilloma in a dog]]
Individual papillomavirus types tend to be highly adapted to replication in a single animal species. In one study, researchers swabbed the forehead skin of a variety of zoo animals and used [[polymerase chain reaction|PCR]] to amplify any papillomavirus DNA that might be present.<ref name="pmid12438579">{{cite journal |vauthors=Antonsson A, Hansson BG |title=Healthy skin of many animal species harbors papillomaviruses which are closely related to their human counterparts |journal=Journal of Virology |volume=76 |issue=24 |pages=12537–42 |date=December 2002 |pmid=12438579 |pmc=136724 |doi=10.1128/JVI.76.24.12537-12542.2002 }}</ref> Although a wide variety of papillomavirus sequences were identified in the study, the authors found little evidence for inter-species transmission. One zookeeper was found to be transiently positive for a chimpanzee-specific papillomavirus sequence. However, the authors note that the chimpanzee-specific papillomavirus sequence could have been the result of surface contamination of the zookeeper's skin, as opposed to productive infection.{{
[[Shope papilloma virus|Cottontail rabbit papillomavirus]] (CRPV) can cause protuberant warts in its native host, the North American rabbit genus ''[[Sylvilagus]]''. These horn-like warts may be the original basis for the [[urban legend]]s of the American antlered rabbit the [[Jackalope]] and European ''[[Wolpertinger]]''.<ref name="Chuck">{{cite web|url= http://sites.lafayette.edu/hollidac/links-for-fun/jackalopes/|title=Prof. Chuck Holliday's www page at Lafayette College » Jackalopes|access-date=2014-07-13|last=Holliday|first=Chuck|url-status=dead|archive-url= https://web.archive.org/web/20140718233931/http://sites.lafayette.edu/hollidac/links-for-fun/jackalopes/|archive-date=2014-07-18}}</ref> European domestic rabbits (genus ''Oryctolagus'') can be transiently infected with CRPV in a laboratory setting. However, since European domestic rabbits do not produce infectious progeny virus, they are considered an incidental or "dead-end" host for CRPV.<ref name="pmid16331841">{{cite journal |vauthors=Christensen ND |title=Cottontail rabbit papillomavirus (CRPV) model system to test antiviral and immunotherapeutic strategies |journal=Antiviral Chemistry & Chemotherapy |volume=16 |issue=6 |pages=355–62 |year=2005 |pmid=16331841 |doi=10.1177/095632020501600602 |doi-access=free }}</ref>
Inter-species transmission has also been documented for [[bovine papillomavirus]] (BPV) type 1.<ref name="pmid2998027">{{cite journal |vauthors=Coggins LW, Ma JQ, Slater AA, Campo MS |title=Sequence homologies between bovine papillomavirus genomes mapped by a novel low-stringency heteroduplex method |journal=Virology |volume=143 |issue=2 |pages=603–11 |date=June 1985 |pmid=2998027 |doi=10.1016/0042-6822(85)90398-8 }}</ref> In its natural host (cattle), BPV-1 induces large fibrous skin warts. BPV-1 infection of horses, which are an incidental host for the virus, can lead to the development of benign tumors known as [[equine sarcoid|sarcoids]]. The agricultural significance of BPV-1 spurred a successful effort to develop a vaccine against the virus.{{
A few reports have identified papillomaviruses in smaller rodents, such as [[Golden hamster|Syrian hamsters]], the African [[Mastomys|multimammate rat]] and the [[Eurasian harvest mouse]].<ref name="pmid1319576">{{cite journal |vauthors=Van Ranst M, Tachezy R, Pruss J, Burk RD |title=Primary structure of the E6 protein of Micromys minutus papillomavirus and Mastomys natalensis papillomavirus |journal=Nucleic Acids Research |volume=20 |issue=11 |pages=2889 |date=June 1992 |pmid=1319576 |pmc=336941 |doi=10.1093/nar/20.11.2889 }}</ref> However, there are no papillomaviruses known to be capable of infecting laboratory [[mouse|mice]]. The lack of a tractable mouse model for papillomavirus infection has been a major limitation for laboratory investigation of papillomaviruses.{{
Four papillomaviruses are known to infect birds: Fringilla coelebs papillomavirus 1, Francolinus leucoscepus papillomavirus 1, Psittacus erithacus papillomavirus 1 and Pygoscelis adeliae papillomavirus 1.<ref name=Varsani2014>{{cite journal |vauthors=Varsani A, Kraberger S, Jennings S, Porzig EL, Julian L, Massaro M, Pollard A, Ballard G, Ainley DG |title=A novel papillomavirus in Adélie penguin (Pygoscelis adeliae) faeces sampled at the Cape Crozier colony, Antarctica |journal=The Journal of General Virology |volume=95 |issue=Pt 6 |pages=1352–65 |date=June 2014 |pmid=24686913 |doi=10.1099/vir.0.064436-0 |s2cid=206218507 |doi-access=free }}</ref> All these species have a gene (E9) of unknown function, suggesting a common origin.
==Evolution==
The evolution of papillomaviruses is thought to be slow compared to many other virus types, but there are no experimental measurements currently available. This is probably because the papillomavirus genome is composed of genetically stable double-stranded DNA that is replicated with high fidelity by the host cell's DNA replication machinery.{{
It is believed that papillomaviruses generally co-evolve with a particular species of host animal over many years, although there are strong evidences against the hypothesis of coevolution.<ref name="MultForce" /><ref name="pmid 21285031">{{cite journal |vauthors=Gottschling M, Göker M, Stamatakis A, Bininda-Emonds OR, Nindl I, Bravo IG |title=Quantifying the phylodynamic forces driving papillomavirus evolution |journal=Molecular Biology and Evolution |volume=28 |issue=7 |pages=2101–13 |date=July 2011 |pmid=21285031 |doi=10.1093/molbev/msr030 |doi-access=free }}</ref> In a particularly speedy example, HPV-16 has evolved slightly as human populations have expanded across the globe and now varies in different geographic regions in a way that probably reflects the history of human migration.<ref name="pmid8411343">{{cite journal |vauthors=Ho L, Chan SY, Burk RD, Das BC, Fujinaga K, Icenogle JP, Kahn T, Kiviat N, Lancaster W, Mavromara-Nazos P |title=The genetic drift of human papillomavirus type 16 is a means of reconstructing prehistoric viral spread and the movement of ancient human populations |journal=Journal of Virology |volume=67 |issue=11 |pages=6413–23 |date=November 1993 |pmid=8411343 |pmc=238076 |doi= 10.1128/JVI.67.11.6413-6423.1993}}</ref><ref name="pmid16227283">{{cite journal |vauthors=Calleja-Macias IE, Villa LL, Prado JC, Kalantari M, Allan B, Williamson AL, Chung LP, Collins RJ, Zuna RE, Dunn ST, Chu TY, Cubie HA, Cuschieri K, von Knebel-Doeberitz M, Martins CR, Sanchez GI, Bosch FX, Munoz N, Bernard HU |title=Worldwide genomic diversity of the high-risk human papillomavirus types 31, 35, 52, and 58, four close relatives of human papillomavirus type 16 |journal=Journal of Virology |volume=79 |issue=21 |pages=13630–40 |date=November 2005 |pmid=16227283 |pmc=1262609 |doi=10.1128/JVI.79.21.13630-13640.2005 }}</ref> Cutaneotropic HPV types are occasionally exchanged between family members during the entire lifetime, but other donors should also be considered in viral transmission.<ref name="FamInfect">{{cite journal |vauthors=Gottschling M, Göker M, Köhler A, Lehmann MD, Stockfleth E, Nindl I |title=Cutaneotropic β-/γ-HPV types are rarely shared between family members |journal=Journal of Investigative Dermatology |year=2009 |volume=129 |issue=10 |pages=2427–34 |doi=10.1038/jid.2009.94 |pmid=19516265 |doi-access=free }}</ref>
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The most recent common ancestor of this group of viruses has been estimated to have existed {{Ma|424}}.<ref>Willemsen A, Bravo IG (2019) Origin and evolution of papillomavirus (onco)genes and genomes. Philos Trans R Soc Lond B Biol Sci. 374(1773):20180303</ref>
There are five main genera infecting humans (Alpha, Beta, Gamma, Mu and Nu). The most recent common ancestor of these genera evolved {{Ma|49.7}}-{{Ma|58.5}}.<ref name=Murahwa2019>Murahwa AT, Nindo F, Onywera H, Meiring TL, Martin DP, Williamson AL (2019) Evolutionary dynamics of ten novel Gamma-PVs: insights from phylogenetic incongruence, recombination and phylodynamic analyses. BMC Genomics 20(1):368</ref> The most recent ancestor of the gamma genus was estimated to have evolved between {{Ma|45.3}} and {{Ma|67.5}}.{{
== Structure ==
[[Image:Bovine Papillomavirus Capsid.png|thumb|Papillomavirus capsid from bovine papillomavirus]]
Papillomaviruses are non-enveloped, meaning that the outer shell or [[capsid]] of the virus is not covered by a lipid [[Cell membrane|membrane]]. A single viral protein, known as L1, is necessary and sufficient for formation of a 55–60 nanometer capsid composed of 72 star-shaped capsomers (see figure). Like most non-enveloped viruses, the capsid is geometrically regular and presents [[icosahedral symmetry]]. Self-assembled [[virus-like particle]]s composed of L1 are the basis of a successful group of prophylactic [[HPV vaccine]]s designed to elicit virus-neutralizing [[antibodies]] that protect against initial HPV infection. As such, papillomaviridæ are stable in the [[Environment (biophysical)|environment]].{{citation needed|date=November 2022}}
The papillomavirus genome is a double-stranded circular DNA molecule ~8,000 [[base pairs]] in length. It is packaged within the L1 shell along with cellular [[histone]] proteins, which serve to wrap and condense DNA.{{citation needed|date=November 2022}}
The papillomavirus capsid also contains a viral protein known as L2, which is less abundant. Although not clear how L2 is arranged within the virion, it is known to perform several important functions, including facilitating the packaging of the viral genome into nascent virions as well as the infectious entry of the virus into new host cells. L2 is of interest as a possible target for more broadly protective [[HPV vaccine]]s.
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==Tissue specificity==
Papillomaviruses replicate exclusively in [[keratinocyte]]s. Keratinocytes form the outermost layers of the skin, as well as some [[mucous membrane|mucosal surfaces]], such as the inside of the cheek or the walls of the vagina. These surface tissues, which are known as stratified [[squamous epithelium|squamous epithelia]], are composed of stacked layers of flattened cells. The cell layers are formed through a process known as [[cellular differentiation]], in which keratinocytes gradually become specialized, eventually forming a hard, crosslinked surface that prevents moisture loss and acts as a barrier against pathogens. Less-differentiated keratinocyte stem cells, replenished on the surface layer, are thought to be the initial target of productive papillomavirus infections. Subsequent steps in the viral life cycle are strictly dependent on the process of keratinocyte differentiation. As a result, papillomaviruses can only replicate in body surface tissues.{{citation needed|date=November 2022}}
==Life cycle==
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Papillomaviruses gain access to keratinocyte stem cells through small wounds, known as microtraumas, in the skin or mucosal surface. Interactions between L1 and sulfated sugars on the cell surface promote initial attachment of the virus.<ref name="pmid10026203">{{cite journal |vauthors=Joyce JG, Tung JS, Przysiecki CT, Cook JC, Lehman ED, Sands JA, Jansen KU, Keller PM |title=The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes |journal=The Journal of Biological Chemistry |volume=274 |issue=9 |pages=5810–22 |date=February 1999 |pmid=10026203 |doi=10.1074/jbc.274.9.5810 |doi-access=free }}</ref><ref name="pmid11152531">{{cite journal |vauthors=Giroglou T, Florin L, Schäfer F, Streeck RE, Sapp M |title=Human papillomavirus infection requires cell surface heparan sulfate |journal=Journal of Virology |volume=75 |issue=3 |pages=1565–70 |date=February 2001 |pmid=11152531 |pmc=114064 |doi=10.1128/JVI.75.3.1565-1570.2001 }}</ref> The virus is then able to get inside from the cell surface via interaction with a specific receptor, likely via the alpha-6 beta-4 integrin,<ref name="pmid9032382">{{cite journal |vauthors=Evander M, Frazer IH, Payne E, Qi YM, Hengst K, McMillan NA |title=Identification of the alpha6 integrin as a candidate receptor for papillomaviruses |journal=Journal of Virology |volume=71 |issue=3 |pages=2449–56 |date=March 1997 |pmid=9032382 |pmc=191355 |doi= 10.1128/JVI.71.3.2449-2456.1997}}</ref><ref name="pmid10497112">{{cite journal |vauthors=McMillan NA, Payne E, Frazer IH, Evander M |title=Expression of the alpha6 integrin confers papillomavirus binding upon receptor-negative B-cells |journal=Virology |volume=261 |issue=2 |pages=271–9 |date=September 1999 |pmid=10497112 |doi=10.1006/viro.1999.9825 |doi-access=free }}</ref> and transported to membrane-enclosed [[Vesicle (biology)|vesicles]] called [[endosome]]s.<ref name="pmid12202231">{{cite journal |vauthors=Selinka HC, Giroglou T, Sapp M |title=Analysis of the infectious entry pathway of human papillomavirus type 33 pseudovirions |journal=Virology |volume=299 |issue=2 |pages=279–287 |date=August 2002 |pmid=12202231 |doi=10.1006/viro.2001.1493 |doi-access=free }}</ref><ref name="pmid12667809">{{cite journal |vauthors=Day PM, Lowy DR, Schiller JT |title=Papillomaviruses infect cells via a clathrin-dependent pathway |journal=Virology |volume=307 |issue=1 |pages=1–11 |date=March 2003 |pmid=12667809 |doi=10.1016/S0042-6822(02)00143-5 |doi-access=free }}</ref> The capsid protein L2 disrupts the membrane of the endosome through a cationic [[cell-penetrating peptide]], allowing the viral genome to escape and traffic, along with L2, to the cell nucleus.<ref name="pmid16378978">{{cite journal |vauthors=Kämper N, Day PM, Nowak T, Selinka HC, Florin L, Bolscher J, Hilbig L, Schiller JT, Sapp M |title=A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes |journal=Journal of Virology |volume=80 |issue=2 |pages=759–68 |date=January 2006 |pmid=16378978 |pmc=1346844 |doi=10.1128/JVI.80.2.759-768.2006 }}</ref><ref name="pmid15383670">{{cite journal |vauthors=Day PM, Baker CC, Lowy DR, Schiller JT |title=Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=101 |issue=39 |pages=14252–7 |date=September 2004 |pmid=15383670 |pmc=521143 |doi=10.1073/pnas.0404229101 |bibcode=2004PNAS..10114252D |doi-access=free }}</ref><ref>{{Cite journal |doi=10.1016/j.cell.2018.07.031|pmid=30122350| pmc=6128760| title=Cell-Penetrating Peptide Mediates Intracellular Membrane Passage of Human Papillomavirus L2 Protein to Trigger Retrograde Trafficking| journal=Cell| volume=174| issue=6| pages=1465–1476.e13| year=2018| last1=Zhang| first1=Pengwei| last2=Monteiro Da Silva| first2=Gabriel| last3=Deatherage| first3=Catherine| last4=Burd| first4=Christopher| last5=Dimaio| first5=Daniel}}</ref>
===Viral persistence and latency===
After successful infection of a keratinocyte, the virus expresses E1 and E2 proteins, which are for replicating and maintaining the viral DNA as a circular [[episome]]. The viral [[oncogene]]s E6 and E7 promote cell growth by inactivating the tumor suppressor proteins [[p53]] and [[retinoblastoma protein|pRb]]. Keratinocyte stem cells in the epithelial basement layer can maintain papillomavirus genomes for decades.<ref name="pmid15753007"/>
===Production of progeny virus===
The current understanding is that viral DNA replication likely occurs in the [[G2 phase|G<sub>2</sub> phase]] of the cell cycle and rely on [[recombination-dependent replication]] supported by [[DNA repair|DNA damage response]] mechanisms (activated by the E7 protein) to produce progeny viral genomes.<ref name=McBride2017>{{cite Q |1=Q39186071}}</ref> Papillomavirus genomes are sometimes integrated into the host genome, especially noticeable with oncogenic HPVs, but is not a normal part of the virus life cycle and a dead-end that eliminates the potential of viral progeny production.<ref name=McBride2017/>
The expression of the viral late genes, L1 and L2, is exclusively restricted to differentiating keratinocytes in the outermost layers of the skin or mucosal surface. The increased expression of L1 and L2 is typically correlated with a dramatic increase in the number of copies of the viral genome. Since the outer layers of stratified [[squamous epithelia]] are subject to relatively limited surveillance by cells of the immune system, it is thought that this restriction of viral late gene expression represents a form of immune evasion.▼
▲The expression of the viral late genes, L1 and L2, is exclusively restricted to differentiating keratinocytes in the outermost layers of the skin or mucosal surface. The increased expression of L1 and L2 is typically correlated with a dramatic increase in the number of copies of the viral genome. Since the outer layers of stratified [[squamous epithelia]] are subject to relatively limited surveillance by cells of the immune system, it is thought that this restriction of viral late gene expression represents a form of immune evasion.{{citation needed|date=November 2022}}
New infectious progeny viruses are assembled in the [[cell nucleus]]. Papillomaviruses have evolved a mechanism for releasing virions into the environment. Other kinds of non-enveloped animal viruses utilize an active [[lytic]] process to kill the host cell, allowing release of progeny virus particles. Often this lytic process is associated with [[inflammation]], which might trigger immune attack against the virus. Papillomaviruses exploit [[desquamation]] as a stealthy, non-inflammatory release mechanism.{{citation needed|date=November 2022}}
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The fact that the papillomavirus life cycle strictly requires keratinocyte differentiation has posed a substantial barrier to the study of papillomaviruses in the laboratory, since it has precluded the use of conventional [[cell culture|cell lines]] to grow the viruses. Because infectious BPV-1 virions can be extracted from the large warts the virus induces on cattle, it has been a workhorse model papillomavirus type for many years. CRPV, rabbit oral papillomavirus (ROPV) and canine oral papillomavirus (COPV) have also been used extensively for laboratory studies. As soon as researchers discovered that these viruses cause cancer, they worked together to find a vaccine to it. Currently, the most effective way to go about it is to mimic a virus that is composed of L1 protein but lack the DNA. Basically, our immune system builds defenses against infections, but if these infections do not cause disease they can be used as a vaccine. PDB entry 6bt3 shows how antibodies surfaces attack the surface of the virus to disable it.<ref>{{cite journal|title=High-Resolution Structure Analysis of Antibody V5 Conformational Epitope on Human Papillomavirus 16|vauthors=Guan J, Bywaters SM, Brendle SA, Ashley RE, Makhov AM, Conway JF, Christensen ND, Hafenstein S|date=6 December 2017|journal=Viruses|volume=9|issue=12|page=374|doi=10.3390/v9120374|pmc=5744149|pmid=29211035|doi-access=free}}</ref>
Some sexually transmitted HPV types have been propagated using a mouse "xenograft" system, in which HPV-infected human cells are implanted into [[scid mouse|immunodeficient mice]]. More recently, some groups have succeeded in isolating infectious HPV-16 from human cervical lesions. However, isolation of infectious virions using this technique is arduous and the yield of infectious virus is very low.{{citation needed|date=November 2022}}
The differentiation of keratinocytes can be mimicked ''in vitro'' by exposing cultured keratinocytes to an air/liquid interface. The adaptation of such "raft culture" systems to the study of papillomaviruses was a significant breakthrough for ''in vitro'' study of the viral life cycle.<ref name="pmid1323879">{{cite journal |vauthors=Meyers C, Frattini MG, Hudson JB, Laimins LA |title=Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation |journal=Science |volume=257 |issue=5072 |pages=971–3 |date=August 1992 |pmid=1323879 |doi=10.1126/science.1323879 |bibcode=1992Sci...257..971M }}</ref> However, raft culture systems are relatively cumbersome and the yield of infectious HPVs can be low.<ref name="pmid15110519">{{cite journal |vauthors=McLaughlin-Drubin ME, Christensen ND, Meyers C |title=Propagation, infection, and neutralization of authentic HPV16 virus |journal=Virology |volume=322 |issue=2 |pages=213–9 |date=May 2004 |pmid=15110519 |doi=10.1016/j.virol.2004.02.011 |doi-access=free }}</ref>
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==Genetic organization and gene expression==
[[Image:HPV-16 genome organization.png|thumb|350px|Genome organization of Human papillomavirus type 16]]<ref name="Zheng">{{cite journal |vauthors=Zheng ZM, Baker CC |title=Papillomavirus genome structure, expression, and post-transcriptional regulation |journal=Frontiers in Bioscience |volume=11 |pages=2286–302 |date=September 2006 |pmid=16720315 |pmc=1472295 |doi=10.2741/1971 }}</ref>
The papillomavirus genome is divided into an early region (E), encoding six open reading frames (ORF) (E1, E2, E4, E5, E6, and E7) that are expressed immediately after initial infection of a host cell, and a late region (L) encoding a major capsid protein L1 and a minor capsid protein L2. All viral ORFs are encoded on one DNA strand (see figure). This represents a dramatic difference between papillomaviruses and [[polyomavirus]]es, since the latter virus type expresses its early and late genes by bi-directional [[transcription (genetics)|transcription]] of both DNA strands. This difference was a major factor in establishment of the consensus that papillomaviruses and polyomaviruses probably never shared a common ancestor, despite the striking similarities in the structures of their virions.{{citation needed|date=November 2022}}
After the host cell is infected, HPV16 early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA contains three exons and two introns and undergoes active RNA splicing to generate multiple isoforms of mRNAs.<ref name="Zheng" /> One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 oncoprotein.<ref name="Tang">{{cite journal |vauthors=Tang S, Tao M, McCoy JP, Zheng ZM |title=The E7 oncoprotein is translated from spliced E6*I transcripts in high-risk human papillomavirus type 16- or type 18-positive cervical cancer cell lines via translation reinitiation |journal=Journal of Virology |volume=80 |issue=9 |pages=4249–63 |date=May 2006 |pmid=16611884 |pmc=1472016 |doi=10.1128/JVI.80.9.4249-4263.2006 }}</ref> In contrast, an intron in the E6 ORF that remains intact without splicing is necessary for translation of E6 oncoprotein.<ref name="Tang" /> However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy.{{citation needed|date=November 2022}}
A major viral late promoter in viral early region becomes active only in differentiated cells and its activity can be highly enhanced by viral DNA replication. The late transcript is also a polycistronic RNA which contains two introns and three exons. Alternative RNA Splicing of this late transcript is essential for L1 and L2 expression and can be regulated by RNA cis-elements and host splicing factors.<ref name="Zheng" /><ref name="Wang">{{cite journal |vauthors=Wang X, Meyers C, Wang HK, Chow LT, Zheng ZM |title=Construction of a full transcription map of human papillomavirus type 18 during productive viral infection |journal=Journal of Virology |volume=85 |issue=16 |pages=8080–92 |date=August 2011 |pmid=21680515 |pmc=3147953 |doi=10.1128/JVI.00670-11 }}</ref><ref name="Jia">{{cite journal |vauthors=Jia R, Liu X, Tao M, Kruhlak M, Guo M, Meyers C, Baker CC, Zheng ZM |title=Control of the papillomavirus early-to-late switch by differentially expressed SRp20 |journal=Journal of Virology |volume=83 |issue=1 |pages=167–80 |date=January 2009 |pmid=18945760 |pmc=2612334 |doi=10.1128/JVI.01719-08 }}</ref>
==Technical discussion of papillomavirus gene functions==
Genes within the papillomavirus genome are usually identified after similarity with other previously identified genes. However, some spurious [[open reading frame]]s might have been mistaken as [[gene]]s simply after their position in the genome, and might not be true genes. This applies specially to certain E3, E4, E5 and E8 [[open reading frame]]s.{{citation needed|date=November 2022}}
===E1===
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===E6===
[[Image:2i0i bio r 250.jpg|thumb|Structure of Sap97 PDZ3 bound to the C-terminal peptide of HPV18 E6<ref>
E6 is a 151 amino-acid peptide that incorporates a type 1 motif with a [[consensus sequence]] –(T/S)-(X)-(V/I)-COOH.<ref name=Gupta>{{cite journal |vauthors=Gupta S, Takhar PP, Degenkolbe R, Koh CH, Zimmermann H, Yang CM, Guan Sim K, Hsu SI, Bernard HU |title=The human papillomavirus type 11 and 16 E6 proteins modulate the cell-cycle regulator and transcription cofactor TRIP-Br1 |journal=Virology |volume=317 |issue=1 |pages=155–64 |date=December 2003 |pmid=14675634 |doi=10.1016/j.virol.2003.08.008 |doi-access=free }}</ref><ref name=Glaun>{{cite journal |vauthors=Glaunsinger BA, Lee SS, Thomas M, Banks L, Javier R |title=Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins |journal=Oncogene |volume=19 |issue=46 |pages=5270–80 |date=November 2000 |pmid=11077444 |pmc=3072458 |doi=10.1038/sj.onc.1203906 }}</ref> It also has two [[zinc finger]] motifs.<ref name=Gupta />
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===E7===
In most papillomavirus types, the primary function of the E7 protein is to inactivate members of the [[retinoblastoma protein|pRb]] family of tumor suppressor proteins. Together with E6, E7 serves to prevent cell death ([[apoptosis]]) and promote [[cell cycle]] progression, thus priming the cell for replication of the viral DNA. E7 also participates in immortalization of infected cells by activating cellular [[telomerase]]. Like E6, E7 is the subject of intense research interest and is believed to exert a wide variety of other effects on infected cells. As with E6, the ongoing expression of E7 is required for survival of cancer cell lines, such as [[HeLa]], that are derived from HPV-induced tumors.<ref name="pmid16500131">{{cite journal |vauthors=Nishimura A, Nakahara T, Ueno T, Sasaki K, Yoshida S, Kyo S, Howley PM, Sakai H |title=Requirement of E7 oncoprotein for viability of HeLa cells |journal=Microbes and Infection |volume=8 |issue=4 |pages=984–93 |date=April 2006 |pmid=16500131 |doi=10.1016/j.micinf.2005.10.015 |doi-access=free }}</ref>
===E8===
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{{Portal|Medicine|Viruses}}
* [[Deer cutaneous fibroma]]
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== References ==
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* Los Alamos National Laboratory maintains a comprehensive (albeit somewhat dated) papillomavirus sequence [https://web.archive.org/web/20060925035907/http://hpv-web.lanl.gov/stdgen/virus/cgi-bin/hpv_organisms.cgi?dbname=hpv database]. This useful database provides detailed descriptions and references for various papillomavirus types.
* A short video which shows [http://www.koreus.com/video/homme-arbre.html the effects of papillomavirus] on the skin of an Indonesian man with [[epidermodysplasia verruciformis]], the genetic inability to defend against some types of cutaneous HPV.
* [https://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/fs_index.htm Best Joint Supplement That Actually Works for Men, Women and Knee] de Villiers, E.M., Bernard, H.U., Broker, T., Delius, H. and zur Hausen, H. Index of Viruses – Papillomaviridae (2006). In: ICTVdB – The Universal Virus Database, version 4. Büchen-Osmond, C (Ed), Columbia University, New York, USA.
* [https://web.archive.org/web/20080227013223/http://phene.cpmc.columbia.edu/ICTVdB/00.099.htm 00.099. Papillomaviridae description] In: ICTVdB – The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA
* [https://web.archive.org/web/20141009131047/http://visualscience.ru/en/projects/human-papillomavirus/illustration/ Human papillomavirus particle and genome visualization]
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{{Human papillomavirus}}
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[[Category:Papillomavirus| ]]
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