Abbreviations : Report Help
Koenraad Van Doorslaer, Zigui Chen, Hans-Ulrich Bernard, Paul K. S. Chan, Rob DeSalle, Joakim Dillner, Ola Forslund, Takeshi Haga, Alison A. McBride8, Luisa L. Villa and Robert D. Burk
A summary of this ICTV Report chapter has been published as an ICTV Virus Taxonomy Profile article in the Journal of General Virology, and should be cited when referencing this online chapter as follows:
Van Doorslaer, K., Chen, Z., Bernard, H., Chan, P.K.S, DeSalle, R., Dillner, J., Forslund, O., Haga, T., McBride, A.A., Villa, L.L., Burk, R.D., and ICTV Report Consortium. 2018, ICTV Virus Taxonomy Profile: Papillomaviridae, Journal of General Virology, 99, 989–990.
The Papillomaviridae is a family of small, non-enveloped viruses with double stranded DNA genomes of 5,748 bp to 8,607 bp. Their classification is based on pairwise nucleotide sequence identity across the L1 open reading frame. Members of the Papillomaviridae primarily infect mucosal and keratinized epithelia, and have been isolated from fish, reptiles, birds and mammals. Despite a long co-evolutionary history with their hosts, some papillomaviruses are pathogens of their natural host species.
Table 1.Papillomaviridae. Characteristics of the family Papillomaviridae.
human papillomavirus 16 (K02718), species Alphapapillomavirus 9, genus Alphapapillomavirus, subfamily Firstpapillomavirinae
Non-enveloped, 55 nm, icosahedral
Circular dsDNA. Genome varies from 5,748 bp to 8,607 bp.
Bidirectional theta replication
Early and late transcripts, alternative splicing, alternative open reading frames
Mammals, reptiles, birds, and fish
Two subfamilies include >50 genera and >130 species
Papillomavirus virions are non-enveloped. The viral capsid is ~600 Å in diameter and consists of 360 copies (arranged as 72 pentamers) of the major capsid protein, L1, and ~12 molecules of the L2 minor capsid protein (Figure 1.Papillomaviridae; (Finnen et al., 2003)). Expression of recombinant L1 with or without L2 allows for self-assembly of virus-like particles (VLPs). Each capsid packages a single copy of the viral circular dsDNA. The packaged viral DNA is associated with core histone proteins (Larsen et al., 1987).
The virion Mr is 47×106. Buoyant density of virions in sucrose and CsCl gradients is 1.20 and 1.34–1.35 g cm−3, respectively. Virion S20,W is 300. Virions are resistant to a wide array of environmental and chemical treatments (Meyers et al., 2014).
The papillomavirus genome is approximately 7,500 bp. Viral genomes vary from 5,748 bp (Sparus aurata papillomavirus type 1; SaPV1) to 8,607 bp (canine papillomavirus type 1; CPV1). The genomes have an average GC content of about 42% (36–59%).
Papillomavirus gene expression is tightly regulated at the level of transcription and RNA processing, including alternative mRNA polyadenylation and splicing (Schwartz 2013). A typical papillomavirus encodes six to nine proteins (Figure 2.Papillomaviridae). However, the ancestral papillomavirus may have only contained a core set of four proteins (E1, E2, L1, and L2). Temporal expression of the viral genome is associated with tissue differentiation (Figure 3.Papillomaviridae). The viral DNA helicase (E1) is the only viral enzyme, and is essential for replication and amplification of the viral chromosome in the nucleus of infected cells. (Bergvall et al., 2013). The viral E2 protein is the master regulator of the viral life cycle, and plays key roles in transcriptional regulation, initiation of DNA replication and partitioning the viral genome (McBride 2013). The E1^E4 gene product is typically translated from a spliced mRNA fusing approximately the first four E1 codons to the E4 ORF, present in an alternative reading frame to the E2 ORF (Doorbar 2013). A subset of viral mRNA encodes a short, hydrophobic, transmembrane protein, E5. Other than hydrophobicity, there is low sequence similarity among different E5 proteins (DiMaio and Petti 2013). The E5 proteins can be further divided into different classes based on phylogeny and hydrophobic profiles (Bravo and Alonso 2004). E5 proteins are typically encoded in the 3ʹ-end of the early coding region. However, hydrophobic proteins, located in other parts of the viral genome have also been described. Designated as E10, these non-E5 hydrophobic proteins either overprint the E6 ORF, or are located in this region in the absence of an E6 gene (Van Doorslaer and McBride 2016). The productive phase of the viral life cycle occurs in differentiated cells that have exited the cell cycle. In order to complete the viral life cycle, the virus needs to uncouple replication from differentiation (Figure 3). The E6 and E7 proteins have been shown to play key roles in usurping the cellular environment to allow for replication. The E6 protein contains two zinc-binding motifs essential for its function (Vande Pol and Klingelhutz 2013). The E7 amino terminus contains regions of similarity to conserved regions (CR) 1 and CR2 of the mastadenovirus E1A protein, and the polyomavirus large T antigen (Roman and Munger 2013). The E7 C-terminus contains a single zinc-binding motif homologous to the E6 motifs (Van Doorslaer 2013). The E6 and E7 proteins appear to be essential for members of the genus Alphapapillomavirus. Remarkably, the E6 and E7 proteins are not encoded by all papillomaviruses (Van Doorslaer 2013). The E8 exon is embedded within E1, and utilizes the same splice acceptor site as E1^E4 mRNA, generating mRNA for the E8^E2 protein. The E8^E2 viral repressor protein is present in essentially every known papillomavirus. E8^E2 inhibits viral replication and gene expression. Upon cellular differentiation, the viral capsid proteins L1 and L2 are expressed. The major capsid protein L1 is the structural component of the viral capsid (Buck et al., 2013). The minor capsid protein L2 plays an active role in viral assembly and throughout the infectious process (Wang and Roden 2013).
Transcription of the circular virus genome occurs from only one DNA strand. The viral genome can be divided into three functional regions. The early region encodes viral proteins involved in transcription, replication, and manipulation of the cellular milieu. The late region encodes the capsid proteins L1, and L2. The upstream regulatory region (URR or LCR) is located between the L1 and E6 ORFs and contains the viral origin of replication as well as binding sites for viral and cellular transcription factors.
The viral replication cycle consists of three distinct phases of replication. Initial limited viral DNA amplification is supported by the viral E1 and E2 replication proteins. The viral E2 protein binds to its binding sites in the viral origin of replication, recruiting the viral E1 helicase allowing for replication. This initial burst of replication is followed by maintenance replication, during which the viral genome is maintained at a relatively low, but constant copy number in the proliferating cells of a clonally expanded population of infected cells. Finally, as an infected cell completes cellular differentiation, there is a switch towards differentiation-dependent genome amplification and eventual generation of progeny virions (McBride 2008). During maintenance replication, the virus needs to establish an S-phase like state in differentiated cells. Through a plethora of protein-protein interactions, the viral E6 and E7 proteins usurp the cellular environment, allowing for viral replication in differentiated cells. Remarkably, recent work has highlighted that different genera may induce this pseudo-S-phase through different mechanisms (White et al., 2012, Meyers et al., 2017, Brimer et al., 2017). The maintenance phase of the viral life cycle can last for months to years. In addition to regulating replication, the viral E2 protein plays a key role during maintenance by ensuring that the viral genomes are faithfully partitioned into the daughter cells. In the top layers of the differentiated epithelia, the viral DNA is amplified to a high copy number. The vegetative phase of the viral life-cycle requires the cellular DNA Damage Response (Bristol et al., 2017). The viral capsid proteins self-assemble into particles encapsidating the viral DNA. As the cells slough off into the environment, infectious virions are released, completing the viral life cycle.
Antigenicity is primarily determined by the major capsid protein, L1. Following vaccination, neutralizing epitopes typically map to a single variable loop (Ludmerer et al., 1997), or more commonly two non-contiguous loops (McClements et al., 2001, Christensen et al., 2001). Viral immunity appears to be highly species-specific, and there is only limited cross-protection, even to types within the same viral species. Furthermore, following natural infection, only approximately half of women seroconvert within 18 months following exposure (Carter et al., 2000). Prophylactic vaccines induce high-titer neutralizing antibodies restricted to a subset of (oncogenic) types within the genus Alphapapillomavirus. The current vaccines do not protect against types belonging to different genera. Vaccination with L2 (minor capsid protein) derived vaccines induces low-titer, yet broadly cross-neutralizing antibodies to heterologous PV types. These vaccines provide cross-protection in animal challenge models (Schellenbacher et al., 2017). Efforts to broaden the human papillomavirus (HPV) vaccines using L2 (poly)-peptides are currently underway (Schellenbacher et al., 2017).
Epidemiological and biological data is primarily available for the viral types belonging to the genus Alphapapillomavirus, and specifically those viruses associated with (cervical) cancer. An estimated 79 million Americans are infected, with an additional 14 million new HPV infections occurring every year (CDC 2017). HPV is spread by skin-to-skin contact, and infections with genital human papillomaviruses are the most common sexually transmitted infection (STI).
Papillomaviruses primarily infect epithelial cells. Following a micro-abrasion, the incoming virion complexes with extracellular heparin sulfate proteoglycans on the basement membrane. This interaction results in conformational changes in the L1 and L2 capsid proteins, in turn allowing for the transfer of the virion to an unknown entry receptor. Following furin cleavage of L2, the virion becomes internalized using a process that shares similarities with macropinocytosis (Campos 2017). Early trafficking events involve transporting virions from early endosomes into acidic late endosome and multivesicular bodies. This allows for capsid disassembly and uncoating. During this process, the viral DNA is believed to remain bound to L2. The L2-DNA complex traffics to the trans-Golgi network, remaining there until the onset of mitosis. During mitosis, the trans-Golgi network naturally vesiculates, and the vesicle-bound viral DNA finds its way into the nucleus. By metaphase, the viral DNA is associated with host chromosomes. Following mitosis, the viral DNA can be seen to be associated with nuclear ND10 bodies (Campos 2017).
As the life cycle is completed in cells already destined for cell death, papillomaviruses are not viremic and are hidden from the immune system. In addition, papillomaviruses have evolved a plethora of mechanisms actively limiting the interferon response, a key antiviral defense mechanism (Kanodia et al., 2007). Overall, papillomaviruses appear to effectively evade the innate immune response, thereby delaying the activation of adaptive immunity. In turn, this likely plays an important role in persistence of the virus for months or even years.
Healthy skin harbors a large spectrum of different papillomavirus types belonging to different genera. While the majority of viral infections are subclinical, certain viral types cause (cervical, anal and/or oral pharyngeal) cancers, and have been associated with an increasing number of squamous cell carcinomas at specific sites. Based on their tropism, papillomaviruses can be roughly divided into cutaneous or mucocutaneous. Epidemiologically, the mucocutaneous HPV types can be further subdivided based on whether they are associated with benign or malignant lesions (Cubie 2013). Importantly, even in the case of viral types associated with specific pathologies, the majority of infections still present as subclinical. In the cervical environment, approximately 90% of HPV infections are cleared within two years post infection. Where clearance depends on an effective cell-mediated immune response, it is not clear why some infections are able to persist. Importantly, in the case of the oncogenic alphapapillomavirus types, persistent infection, not an incident infection is the main risk factor for progression towards cancer (Burk et al., 2009). Indeed, cellular transformation and viral replication are mutually exclusive, suggesting that oncogenic progression is not a typical outcome of infection.
The current taxonomic classification of papillomaviruses is based on the nucleotide sequence of the L1 ORF. The L1 ORF of members of different subfamilies shares less than 45% sequence identity.
The original criteria distinguishing genera stated: “Most types within a PV genus show less than 60% sequence identity to types of other genera based on global multiple sequence or pairwise alignments of the L1 genes. Nevertheless, the suggested percentage identities that define PV genera have to be taken as general, but not absolute criteria as curation is necessary” (de Villiers et al., 2004). Practically, papillomavirus genera are primarily delineated by visual inspection of phylogenetic trees derived from concatenated E1, E2, L1, and L2 nucleotide sequences. Efforts are underway to refine the papillomavirus classification scheme.
Papilloma: from Latin papilla, “nipple, pustule”, and Greek suffix -oma, used to form nouns denoting “tumors”. Viral genera belonging to the subfamily of the Firstpapillomavirinae are named according to the Greek alphabet (e.g., Alphapapillomavirus). The prefixes “Dyo-” and “Treis-” are used to accommodate the growing list of viral genera within this subfamily. The names Alphapapillomavirus, Betapapillomavirus, and Gammapapillomavirus have been used for the genera containing papillomaviruses that infect humans and are not used in combination with the Dyo- or Treis- prefixes. Genera within the Secondpapillomavirinae are named according to the Semitic abjads. Currently, the Secondpapillomavirinae contain a single genus, bearing the first letter of this alphabet (transcribed as “A” in Latin): Alefpapillomavirus.
Phylogenetic analysis of papillomaviruses based on the concatenated alignment of four coding sequences (E1, E2, L2, and L1) from isolates from the type species of each of the 53 genera (Figure 4. Papillomaviridae) supports the existence of at least two distinct subfamilies (Firstpapillomavirinae and Secondpapillomavirinae). Likewise, this phylogeny, and that of an analysis of all 133 species (tree available in Resources), corroborates many genera and species within the Firstpapillomavirinae. However, not all genera or species are equally supported. There may be a need in the near future to base the taxonomy of the Papillomaviridae on the phylogenetic tree.
There is evidence of recombination between a polyomavirus and a papillomavirus. The unclassified bandicoot papillomatosis carcinomatosis virus types 1 and 2 (BPCV1 and BPCV2) have circular dsDNA genomes encoding large and small T antigens related to avian polyomaviruses and capsid proteins (L1 and L2) of a putative marsupial papillomavirus.
The papillomaviruses within the subfamily Firstpapillomavirinae are associated with amniote (reptile, bird, and mammalian) hosts. These viruses contain the core viral proteins (E1, E2, L1, and L2) and at least one additional accessory protein (E5, E6 or E7).
Members of this genus preferentially infect the oral or anogenital mucosa in humans and primates. Members of certain species (e.g. Alphapapillomavirus 2 and Alphapapillomavirus 4) are also found in lesions of cutaneous sites. Specific members of certain species (e.g. Alphapapillomavirus 7 and Alphapapillomavirus 9) are considered as oncogenic in view of their regular presence in malignant tissue. All members of this genus code for a hydrophobic E5 protein, located at the 3′-end of the early region.
See discussion under family description.
See discussion under family description.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% nucleotide identity across the L1 ORF to papillomaviruses within the genus (Figure 1.Alphapapillomavirus).
human papillomavirus mEV06c12b
Members of this genus typically cause latent infections. However, in patients with specific (immune) disorders, members of this genus can cause warts or progress to cutaneous squamous cell carcinomas (SCC). Patients suffering from the rare disease epidermodysplasia verruciformis (EV) are at a higher risk of developing SCC, and certain members of the genus Betapapillomavirus have been implicated (Arnold and Hofbauer 2012). Recent evidence suggests that, in the general population, certain betapapillomavirus types may be a co-factor in the development of SCC. Remarkably, these betapapillomavirus types are not detected in most SSC, suggesting that viral proteins may not be required to maintain the malignant SCC lesions. Members of the genus Betapapillomavirus are also the most common human papillomavirus (HPV) types found in the human oral cavity and some have been prospectively associated with oropharyngeal cancer development (Agalliu et al., 2016).
See discussion under family description.
See discussion under family description.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Betapapillomavirus).
human papillomavirus mEV03c09
human papillomavirus mHIVGc36
human papillomavirus mMTS1
human papillomavirus mRTRX7
human papillomavirus mTVMBSFc09
human papillomavirus mTVMBSGc2024
human papillomavirus mm090c09
human papillomavirus mm292c10
human papillomavirus mm292c100
human papillomavirus mm292c14
human papillomavirus mm292c88
human papillomavirus mw15c111
Members of this genus are associated with skin plaques in carnivore hosts.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Chipapillomavirus).
These viruses are associated with fibropapillomas in their respective ungulate hosts. Trans-species transmission occurs, where it induces non-productive sarcoids. The E5 protein, located in the region between the early and late genes, has transforming properties.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Deltapapillomavirus).
The sole member of this genus was isolated from the skin of a donkey (Equus asinus).
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus.
Members of this genus are associated with genital lesions in pigs (Sus scrofa). Members of this genus lack an E7 ORF.
Members of this genus are associated with the healthy skin of yellow-necked spurfowl or yellow-necked francolin (Pternistis leucoscepus) living in Africa, a species of bird in the family Phasianidae. The E6 protein contains a single zinc-binding domain. The genome also encodes for a unique E9 protein (Van Doorslaer et al., 2017b).
Members of this genus are associated with hair follicles of the European hedgehog (Erinaceus europaeus).
Members of this genus are associated with mucosal lesions in horses (Equus caballus).
Members of this genus are associated with the skin lesions of ungulates.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Dyokappapapillomavirus).
Members of this genus are associated with a lesion on an extremely rare marsupial, woylie or brush-tailed bettong (Bettongia penicillata).
Members of this genus are associated with skin lesions on carpet python or diamond python (Morelia spilota).
Members of this genus are associated with skin lesions of sea lions (Zalophus californianus).
Members of this genus were isolated from the oral mucosa of bats.
Members of this genus are associated with oral lesions in a New World monkey, brown howler (Alouatta guariba) and common squirrel monkey (Saimiri sciureus).
Members of this genus were isolated from the healthy skin of a European mole (Talpa europaea).
Members of this genus are associated with genital lesions in cetaceans. There is evidence for (intra-genus) recombination. Members of this genus lack an E7 ORF.
Putative novel PV genome with complete genome sequence data available and being <70% related to PV’s within the genus.
Members of this genus are associated with mucosal lesions in horses.
Members of this genus are associated with a cutaneous exophytic lesion in beavers (Castor canadensis).
Members of this genus are associated with lesions from insectivorous bats.
Members of this genus are associated with a papillomavirus isolated from feline Bowenoid in situ carcinomas.
Members of this genus are associated with lesions from bats.
Members of this genus are associated with skin and teat lesions of cattle.
Members of this genus are associated with the skin lesions of marine turtles. The E6 protein contains a single zinc-binding domain.
Infections are associated with cutaneous papillomas in ungulates.
Members of this genus are associated with cutaneous lesions in birds. Unlike the prototypical E6 protein which contains two zinc-binding motifs, the etapapillomavirus E6 protein contains a single zinc-binding motif. These papillomaviruses contain an E9 protein of unknown function. No E8^E2 or E1^E4 proteins have been identified.
Members of this genus are typically found on the skin and oral mucosa of primates. Infections are usually asymptomatic. However, some infections cause cutaneous lesions in their host and are histologically distinguishable by intracytoplasmic inclusion bodies. The members of the species Gammapapillomavirus 6 do not contain an E6 ORF, but encode a putative E10 protein in the same location.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Gammapapillomavirus).
human papillomavirus mCG2
human papillomavirus mCG3
human papillomavirus mCH2
human papillomavirus mDysk1
human papillomavirus mDysk2
human papillomavirus mDysk3
human papillomavirus mDysk5
human papillomavirus mDysk6
human papillomavirus mEV03c05
human papillomavirus mEV03c104
human papillomavirus mEV03c188
human papillomavirus mEV03c212
human papillomavirus mEV03c40
human papillomavirus mEV03c434
human papillomavirus mEV03c45
human papillomavirus mEV03c60
human papillomavirus mEV06c107
human papillomavirus mEV06c118
human papillomavirus mEV07c367
human papillomavirus mEV07c382
human papillomavirus mEV07c390
human papillomavirus mFD1
human papillomavirus mFD2
human papillomavirus mFS1
human papillomavirus mFi864
human papillomavirus mHIVGc70
human papillomavirus mICB1
human papillomavirus mKC5
human papillomavirus mKN1
human papillomavirus mKN2
human papillomavirus mKN3
human papillomavirus mL55
human papillomavirus mLCOSOc196
human papillomavirus mMTS2
human papillomavirus mSD2
human papillomavirus mSE355
human papillomavirus mSE379
human papillomavirus mSE383
human papillomavirus mTVMBSGc529
human papillomavirus mTVMBSGc2450
human papillomavirus mTVMBSHc13
human papillomavirus mTVMBSHc33
human papillomavirus mTVMBSWc141
human papillomavirus mZJ01
human papillomavirus mdo1c02
human papillomavirus mdo1c232
human papillomavirus mga2c01
human papillomavirus mga2c70
human papillomavirus mm090c10
human papillomavirus mm090c145
human papillomavirus mm090c66
human papillomavirus mw02c24a
human papillomavirus mw03c65
human papillomavirus mw07c34d
human papillomavirus mw07c68b
human papillomavirus mw07c74b
human papillomavirus mw11C24
human papillomavirus mw11C39
human papillomavirus mw11C51
human papillomavirus mw11c13
human papillomavirus mw18c07
human papillomavirus mw18c11d
human papillomavirus mw18c134
human papillomavirus mw18c25
human papillomavirus mw18c39
human papillomavirus mw20c01a
human papillomavirus mw20c01b
human papillomavirus mw20c02c
human papillomavirus mw20c03a
human papillomavirus mw20c04
human papillomavirus mw20c08a
human papillomavirus mw20c09
human papillomavirus mw20c10a
human papillomavirus mw21c693
human papillomavirus mw22c09
human papillomavirus mw23c08c
human papillomavirus mw23c101c
human papillomavirus mw23c77
human papillomavirus mw27c04c
human papillomavirus mw27c157c
human papillomavirus mw27c39c
human papillomavirus mw27c52c
human papillomavirus mw34c04a
human papillomavirus mw34c11a
human papillomavirus mw34c14a
human papillomavirus mw34c28a
human papillomavirus mw34c34a
human papillomavirus mwg1c05
human papillomavirus mwg1c09
These papillomaviruses are associated with cutaneous lesions in rodents.
Members of this genus cause cutaneous and mucosal lesions in rabbits. The E6 ORF is larger than in other genera. The viral genomes contain an E5 and an E10 ORF in the early region.
Members of this genus infect carnivores. The region between the early and late coding regions is exceptionally large.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Lambdapapillomavirus).
Figure 1.Lambdapapillomavirus. Phylogenetic tree of members of the genus Lambdapapillomavirus. The E1, E2, L2, and L1 nucleotide sequences of 343 papillomavirus isolates including representatives of all species and genera within the Papillomaviridae family were aligned as amino acid sequences using MUSCLE v7.221 (Edgar 2004). JModeltest2 (Darriba et al., 2012) was used to determine the optimal model of evolution (GTR + I + G) for the concatenated nucleotide sequences. Maximum likelihood (ML) trees were constructed using RAxML MPI v8.2.9 (Stamatakis 2006) implementing the GTR substitution model. ML bootstrap analysis used the autoMRE-based stopping criterion in RAxML. Following tree construction (tree available in the Resources section of the Papillomaviridae Report), the subtree corresponding to the genus Lambdapapillomavirus was isolated. Tips are labelled with virus names and accession numbers; nodes are labelled with bootstrap support values.
Primate papillomaviruses associated with cutaneous lesions
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus(Figure 1.Mupapillomavirus).
human papillomavirus md01c06
Members of this genus are human papillomaviruses causing benign and malignant cutaneous lesions.
Members of this genus are associated with polar bears (Ursus maritimus). Members of this genus lack an E7 ORF.
Members are associated with genital lesions of cetaceans. No E7 protein is present.
Members of this genus are associated with the healthy skin of goats (Capra hircus).
Members of this genus are associated with cutaneous lesions in rodents.
Members of this genus are associated with cutaneous lesions in bats.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Psipapillomavirus).
Members of this genus are associated with skin lesions on manatees (Trichechus manatus).
Members of this genus are associated with cutaneous lesions of a North American porcupine (Erethizon dorsatum).
Members of this genus are clinically associated with viral plaques in carnivores.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Taupapillomavirus).
Members of the only species in this genus are associated with cutaneous lesions in birds and does not contain an E6 ORF, but contains an E9 protein of unknown function. No E8^E2 or E1^E4 proteins have been identified.
The sole member of this genus was isolated from the healthy skin of an Adélie penguin (Pygoscelis adeliae). The E6 protein contains a single zinc-binding E6 motif. The genome also encodes a unique E9 protein (Van Doorslaer et al., 2017b).
The sole member of this genus is associated with the red fox (Vulpes vulpes).
Members of this genus are associated with insectivorous bats.
Members of this genus are associated with lesions from horses.
The sole member of this genus is associated with the Javan rusa deer (Rusa timorensis).
The sole member of this genus is associated with a cartilaginous lesion of a bird, a northern fulmar (Fulmarus glacialis). The E6 protein contains a single zinc-binding E6 motif.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Upsilonpapillomavirus).
Infections by members of this genus cause true papillomas on the cutaneous or mucosal surfaces of ungulates. Most members of this genus do not encode an E6 protein. All viruses in this genus express an E10 protein from part of the genome typically occupied by E6. The E10 protein displays transforming properties.
Putative novel papillomavirus genome with complete genome sequence data available and that is <70% related to papillomaviruses within the genus (Figure 1.Xipapillomavirus).
Members of this genus produce cutaneous infections in horses.
The exemplar isolate of the single species in the single genus in the Secondpapillomavirinae was isolated from a fish and has the smallest papillomavirus genome known. The genome consists of the core viral proteins (E1, E2, L1, and L2).
The exemplar isolate of the single species in this genus was associated with skin lesions of fish, gilt-head (sea) bream (Sparus aurata).
Koenraad Van Doorslaer* Papillomaviridae Study Group ChairSchool of Animal and Comparative Biomedical Sciences Cancer Biology Graduate Interdisciplinary Program Genetics Graduate Interdisciplinary Program BIO5 Institute, and the University of Arizona Cancer Center University of Arizona, Tucson, AZ, USA E-mail: email@example.com
Zigui Chen Department of Microbiology The Chinese University of Hong Kong Hong Kong SAR, China E-mail: firstname.lastname@example.org
Hans-Ulrich Bernard Department of Molecular Biology and Biochemistry School of Biological Sciences University of California Irvine Irvine, CA, USA E-mail: email@example.com
Chan, Paul Department of Microbiology The Chinese University of Hong Kong Hong Kong SAR, China E-mail: firstname.lastname@example.org
Rob Desalle Sackler Institute for Comparative Genomics American Museum of Natural History Central Park West and 79th St. New York, NY, USA E-mail: email@example.com
Joakim Dillner International HPV Reference Center Department of Laboratory Medicine Karolinska Institutet 14186 Stockholm, Sweden E-mail: firstname.lastname@example.org
Ola Forslund Department of Medical Microbiology Laboratory Medicine, Lund University Sölvegatan 23, Sjukhusområdet, 221 85 Lund, Sweden E-mail: email@example.com
Takeshi Haga The University of Tokyo Division of Infection Control and Disease Prevention, Department of Veterinary Medical Science, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan E-mail: firstname.lastname@example.org
Alison A. McBride Laboratory of Viral Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892, USA E-mail: AMCBRIDE@niaid.nih.gov
Luisa L. Villa Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Instituto do Câncer do Estado de São Paulo Centro de Investigação Translacional em Oncologia Universidade de São Paulo São Paulo, SP, Brazil E-mail: email@example.com
Robert D. Burk Departments of Epidemiology and Population Health, Pediatrics, Microbiology and Immunology, and Obstetrics & Gynecology and Women’s Health Albert Einstein College of Medicine Bronx, NY, USA E-mail: firstname.lastname@example.org
* to whom correspondence should be addressed
The chapter in the Ninth ICTV Report, which served as the template for this chapter, was contributed by Bernard, H.-U., Burk, R.D., deVilliers, E.-M. and zur Hausen, H.
Concatenated E1, E2, L1, L2 alignment – for 53 isolates (one from each type species)
Tree file (newick format)
Alignment file (FASTA format)
Concatenated E1, E2, L1, L2 alignment for 343 isolates
Image (pdf format)
Tree file (tre format)
The Papillomavirus Episteme (PaVE; pave.niaid.nih.gov (Van Doorslaer et al., 2017; Van Doorslaer et al., 2013)) provides centralized access to a special edition of the journal ‘Virology’ (Lambert PF et al., 2013). This special edition combined expert reviews of various papillomavirus-associated topics.
Lambert PF, McBride A & HU, B. (2013).Editorial: Special issue: The Papillomavirus Episteme. Virology 445, 1.
Van Doorslaer, K., Li, Z., Xirasagar, S., Maes, P., Kaminsky, D., Liou, D., Sun, Q., Kaur, R., Huyen, Y. & McBride, A. A. (2017).The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res 45, D499-D506. [PubMed]
Van Doorslaer, K., Tan, Q., Xirasagar, S., Bandaru, S., Gopalan, V., Mohamoud, Y., Huyen, Y. & McBride, A. A. (2013).The Papillomavirus Episteme: a central resource for papillomavirus sequence data and analysis. Nucleic Acids Res 41, D571-D578. [PubMed]
Agalliu, I., Gapstur, S., Chen, Z., Wang, T., Anderson, R. L., Teras, L., Kreimer, A. R., Hayes, R. B., Freedman, N. D. & Burk, R. D. (2016).Associations of oral α-, β-, and γ-human papillomavirus types with risk of incident head and neck cancer. JAMA Oncology 2, 599-606. [PubMed]
Arnold, A. W. & Hofbauer, G. F. (2012).Human papillomavirus and squamous cell cancer of the skin--epidermodysplasia verruciformis-associated human papillomavirus revisited. Curr Probl Dermatol 43, 49-56. [PubMed]
Bergvall, M., Melendy, T. & Archambault, J. (2013).The E1 proteins. Virology 445, 35-56. [PubMed]
Bernard, H. U., Chan, S. Y. & Delius, H. (1994).Evolution of papillomaviruses. Curr Top Microbiol Immunol 186, 33-54. [PubMed]
Bravo, I. G. & Alonso, A. (2004).Mucosal human papillomaviruses encode four different E5 proteins whose chemistry and phylogeny correlate with malignant or benign growth. J Virol 78, 13613-13626. [PubMed]
Brimer, N., Drews, C. M. & Vande Pol, S. B. (2017).Association of papillomavirus E6 proteins with either MAML1 or E6AP clusters E6 proteins by structure, function, and evolutionary relatedness. PLoS Pathog 13, e1006781. [PubMed]
Bristol, M. L., Das, D. & Morgan, I. M. (2017).Why human papillomaviruses activate the DNA damage response (DDR) and how cellular and viral replication persists in the presence of DDR signaling. Viruses 9, E268. [PubMed]
Buck, C. B., Day, P. M. & Trus, B. L. (2013).The papillomavirus major capsid protein L1. Virology 445, 169-174. [PubMed]
Burk, R. D., Chen, Z. & Van Doorslaer, K. (2009).Human papillomaviruses: genetic basis of carcinogenicity. Public Health Genomics 12, 281-290. [PubMed]
Campos, S. K. (2017).Subcellular trafficking of the papillomavirus genome during initial infection: the remarkable abilities of minor capsid protein L2. Viruses 9, E370. [PubMed]
Carter, J. J., Koutsky, L. A., Hughes, J. P., Lee, S. K., Kuypers, J., Kiviat, N. & Galloway, D. A. (2000).Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis 181, 1911-1919. [PubMed]
CDC (2017).Genital HPV Infection—Centers for Disease Control and Prevention Fact Sheet: Genital HPV Infection.
Christensen, N. D., Cladel, N. M., Reed, C. A., Budgeon, L. R., Embers, M. E., Skulsky, D. M., McClements, W. L., Ludmerer, S. W. & Jansen, K. U. (2001).Hybrid papillomavirus L1 molecules assemble into virus-like particles that reconstitute conformational epitopes and induce neutralizing antibodies to distinct HPV types. Virology 291, 324-334. [PubMed]
Cubie, H. A. (2013).Diseases associated with human papillomavirus infection. Virology 445, 21-34. [PubMed]
Darriba, D., Taboada, G. L., Doallo, R. & Posada, D. (2012).jModelTest 2: more models, new heuristics and parallel computing. Nat Methods 9, 772. [PubMed]
de Villiers, E. M., Fauquet, C., Broker, T. R., Bernard, H. U. & zur Hausen, H. (2004).Classification of papillomaviruses. Virology 324, 17-27. [PubMed]
DiMaio, D. & Petti, L. M. (2013).The E5 proteins. Virology 445, 99-114. [PubMed]
Doorbar, J. (2013).The E4 protein; structure, function and patterns of expression. Virology 445, 80-98. [PubMed]
Edgar, R. C. (2004).MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 5, 113. [PubMed]
Finnen, R. L., Erickson, K. D., Chen, X. S. & Garcea, R. L. (2003).Interactions between papillomavirus L1 and L2 capsid proteins. J Virol 77, 4818-4826. [PubMed]
Guan, J., Bywaters, S. M., Brendle, S. A., Ashley, R. E., Makhov, A. M., Conway, J. F., Christensen, N. D. & Hafenstein, S. (2017).Cryoelectron microscopy maps of human papillomavirus 16 reveal L2 densities and heparin binding site. Structure 25, 253-263. [PubMed]
Kanodia, S., Fahey, L. M. & Kast, W. M. (2007).Mechanisms used by human papillomaviruses to escape the host immune response. Curr Cancer Drug Targets 7, 79-89. [PubMed]
Kumar, S., Stecher, G. & Tamura, K. (2016).MEGA7: Molecular Evolutionary Genetics Analysis version 7.0 for bigger datasets. Mol Biol Evol 33, 1870-1874. [PubMed]
Larsen, P. M., Storgaard, L. & Fey, S. J. (1987).Proteins present in bovine papillomavirus particles. J Virol 61, 3596-3601. [PubMed]
Ludmerer, S. W., Benincasa, D., Mark, G. E., 3rd & Christensen, N. D. (1997).A neutralizing epitope of human papillomavirus type 11 is principally described by a continuous set of residues which overlap a distinct linear, surface-exposed epitope. J Virol 71, 3834-3839. [PubMed]
McBride, A. A. (2008).Replication and partitioning of papillomavirus genomes. Adv Virus Res 72, 155-205. [PubMed]
McBride, A. A. (2013).The papillomavirus E2 proteins. Virology 445, 57-79. [PubMed]
McClements, W. L., Wang, X. M., Ling, J. C., Skulsky, D. M., Christensen, N. D., Jansen, K. U. & Ludmerer, S. W. (2001).A novel human papillomavirus type 6 neutralizing domain comprising two discrete regions of the major capsid protein L1. Virology 289, 262-268. [PubMed]
Meyers, J., Ryndock, E., Conway, M. J., Meyers, C. & Robison, R. (2014).Susceptibility of high-risk human papillomavirus type 16 to clinical disinfectants. J Antimicrob Chemother 69, 1546-1550. [PubMed]
Meyers, J. M., Uberoi, A., Grace, M., Lambert, P. F. & Munger, K. (2017).Cutaneous HPV8 and MmuPV1 E6 proteins target the NOTCH and TGF-beta tumor suppressors to inhibit differentiation and sustain keratinocyte proliferation. PLoS Pathog 13, e1006171. [PubMed]
Rector, A., Lemey, P., Tachezy, R., Mostmans, S., Ghim, S. J., Van Doorslaer, K., Roelke, M., Bush, M., Montali, R. J., Joslin, J., Burk, R. D., Jenson, A. B., Sundberg, J. P., Shapiro, B. & Van Ranst, M. (2007).Ancient papillomavirus-host co-speciation in Felidae. Genome Biol 8, R57. [PubMed]
Roman, A. & Munger, K. (2013).The papillomavirus E7 proteins. Virology 445, 138-168. [PubMed]
Schellenbacher, C., Roden, R. B. S. & Kirnbauer, R. (2017).Developments in L2-based human papillomavirus (HPV) vaccines. Virus Res 231, 166-175. [PubMed]
Schwartz, S. (2013).Papillomavirus transcripts and posttranscriptional regulation. Virology 445, 187-196. [PubMed]
Stamatakis, A. (2006).RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics 22, 2688-2690. [PubMed]
Van Doorslaer, K. (2013).Evolution of the Papillomaviridae . Virology 445, 11-20. [PubMed]
Van Doorslaer, K., Li, Z., Xirasagar, S., Maes, P., Kaminsky, D., Liou, D., Sun, Q., Kaur, R., Huyen, Y. & McBride, A. A. (2017a).The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res 45, D499-D506. [PubMed]
Van Doorslaer, K. & McBride, A. A. (2016).Molecular archeological evidence in support of the repeated loss of a papillomavirus gene. Sci Rep 6, 33028. [PubMed]
Van Doorslaer, K., Ruoppolo, V., Schmidt, A., Lescroel, A., Jongsomjit, D., Elrod, M., Kraberger, S., Stainton, D., Dugger, K. M., Ballard, G., Ainley, D. G. & Varsani, A. (2017b).Unique genome organization of non-mammalian papillomaviruses provides insights into the evolution of viral early proteins. Virus Evol 3, vex027. [PubMed]
Van Doorslaer, K., Tan, Q., Xirasagar, S., Bandaru, S., Gopalan, V., Mohamoud, Y., Huyen, Y. & McBride, A. A. (2013).The Papillomavirus Episteme: a central resource for papillomavirus sequence data and analysis. Nucleic Acids Res 41, D571-D578. [PubMed]
Vande Pol, S. B. & Klingelhutz, A. J. (2013).Papillomavirus E6 oncoproteins. Virology 445, 115-137. [PubMed]
Wang, J. W. & Roden, R. B. (2013).L2, the minor capsid protein of papillomavirus. Virology 445, 175-186. [PubMed]
White, E. A., Kramer, R. E., Tan, M. J., Hayes, S. D., Harper, J. W. & Howley, P. M. (2012).Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. J Virol 86, 13174-13186. [PubMed]
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