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. 2022 Sep 12;45(3 Suppl 1):e20210388. doi: 10.1590/1678-4685-GMB-2021-0388

New insights into Canis familiaris papillomaviruses genetics and biology: Is the genetic characterization of CPV types and their variants an important clinical issue?

Jordana Dantas Rodrigues Reis 1, Marcus Vinicius de Aragão Batista 1
PMCID: PMC9469487  PMID: 36095300

Abstract

Canis familiaris papillomavirus (CPV) is a member of the Papillomaviridae family and is found in dogs. After infection, the host can remain asymtomatic or develop benign ephitelial neoplasms such as papillomas and pigmented viral plaques, which can progress to cancer, in the form of squamous cell carcinoma (SCC). In humans, 227 types of human papillomavirus (HPV) have been described, with a well-established risk classification for cancer development. In addition, it is also known that variants of some high-risk HPV types may present different risks in respect of SCC development. In dogs, however, only a few types of CPV have been identified, despite the growing interest in this area, and knowledge on the genetic characterization of CPV variants is still scarce. Recent studies of CPV have shown that, as with HPV, benign neoplasia can develop into cancer, but it is believed that there are many more types and variants still to be described. Therefore, the aim of this study was to describe the genetics and biology of CPV, with the focus on what is known about lesions, geographic localization, virus types and variants.

Keywords: Canine papillomavirus, dogs, genetic diversity, SCC, variant

Introduction

Canis familiaris papillomavirus (CPV) belongs to the extensive family Papillomaviridae that infect vertebrate hosts such as mammals, birds, reptiles and fish (Van Doorslaer et al., 2018). This family has great genetic diversity but, unsurprisingly, the most frequently studied papillomavirus (PV) has been the human papillomavirus (HPV) (Rector and Van Ranst, 2013; Van Doorslaer, 2013).

CPV infection is considered species-specific to dogs, but oral papillomatosis has been described in two members of the same Canidae family that the subspecies Canis lupus familiaris belongs to, namely the wolf and the coyote (Lange and Favrot, 2011). In the USA, a gray wolf with oral papillomatosis was found to be infected with a CPV1 of the species Lambdapapillomavirus 2 (Knowles et al., 2017).

Viral transmission occurs by cutaneous or mucosal contact facilitated by some trauma affecting the basal layer of the skin and the mucosal epithelium that results in neoplastic lesions or asymptomatic infection (Lange et al., 2011; Sykes and Luff, 2014; Sardon et al., 2015). The neoplasms that have been associated with CPV are benign exophytic and endophytic papillomas, and pigmented viral plaques, with progression to malign neoplasia in the form of squamous cell carcinoma (SCC) (Zhou et al., 2014). The disease canine papillomatosis mostly affects young, immunosuppressed dogs with some factors influencing the gravity of the clinical status of the animal, such as its genetic background and the pathogenicity of the PV involved (Lange and Favrot, 2011).

Genome and infection cycle

Papillomavirus (PVs) are double-stranded DNA viruses with a circular genome that can have up to 8,607 bp with a non-enveloped, 55 nm capsid of icosahedral symmetry (Van Doorlslaer et al., 2018). The genome of CPV varies from 7,742 bp (CPV4) to 8,607 bp (CPV1) (Table 1). It has six to eight open reading frames (ORFs): E1, E2, E4, E5, E6, E7 (the early genes), L1 and L2 (the late and structural ones) (Figure 1) (Bernard et al., 2010). Although there are some variations in CPV ORFs, they are translated into proteins that compose the viral capsid and regulate the infection cycle of the virus, which seems to be very similar among all types of PVs.

Table 1 -. Genomic characterization and length variation for each CPV genotype.

CPV type GenBank ID Length E1 E2 E4 E5 E6 E7 L1 L2
CPV1 GI:9627734 8607 816-2609 2551-3708 3104-3463 ______ 102-536 533-826 6837-8348 5288-6829
CPV2 GI:56693036 8101 795-2618 2557-4152 2912-3907 4169-4294 105-512 515-811 6202-7713 4662-6188
CPV3 GI:113200740 7801 732-2618 2560-4011 ______ ______ 25-480 440-742 5757-7259 4219-5736
CPV4 GI:164429763 7742 813-2702 2644-4107 ______ ______ 109-564 524-823 5795-7294 4249-5775
CPV5 GI: 255683764 7810 1132-3021 2963-4432 3429-4193 ______ 422-880 840-1142 6167-7672 4628-6145
CPV6 GI:258611059 8242 706-2517 2459-3625 3036-3389 ______ 13-426 423-716 6368-7876 4823-6358
CPV7 GI:255683756 7955 774-2591 2530-4044 3068-3802 ______ 76-492 494-790 6032-7546 4481-6013
CPV8 GI:347750421 7784 742-2619 2561-4144 3084-3908 ______ 1-435 438-752 5849-7342 4308-5837
CPV9 GI:363540888 7873 970-2835 2777-4240 3348-4001 ______ 263-718 678-980 6051-7556 4481-5998
CPV10 GI:363540896 7774 844-2724 2666-4258 3189-4022 ______ 95-532 543-854 5912-7420 4390-5901
CPV11 GI:348659024 7828 826-2715 2657-4141 3228-3902 4131-4316 95-574 534-836 5889-7388 4338-7388
CPV12 GI:388542469 7890 708-2600 2542-4002 3113-3763 ______ 1-456 416-718 5811-7316 4238-5758
CPV13 GI:402282430 8228 712-2526 2468-3973 2931-3731 ______ 13-438 435-725 6249-7763 4645-6228
CPV14 GI:430025787 7826 829-2703 2654-4273 829-4037 ______ 112-522 525-839 5978-7474 4437-5966
CPV15 GI:429841972 7776 783-2663 2605-4170 ________ ______ 1-507 482-793 5864-7357 4278-5852
CPV16 GI:765702648 7796 702-2594 2536-3957 3107-3718 3978-4124 1-456 416-712 5565-7202 4148-5653
CPV17 GI:974142334 8007 ________ 2462-3952 2928-3707 ______ 1-411 414-710 6003-7523 4451-5986
CPV18 GI:1046841328 7810 861-2750 2692-4143 3158-3904 ______ 154-609 569-871 5896-7398 4355-5872
CPV19 GI:1064859043 7941 699-2543 2482-3954 699-3712 4001-4135 1-417 419-715 5934-7445 4382-5917
CPV20 GI:1008264056 7839 762-2660 2602-4068 3173-3829 3907-4068 1-507 467-772 5832-7331 4294-5808
CPV21 GI:1464250060 8225 684-2525 2467-3921 2834-3361 _______ 1-429 416-697 6185-7705 4636-6171
CPV22 GI:1464250068 8300 694-2511 2453-3934 2919-3692 _______ 1-420 417-707 6321-7835 4737-6305
CPV23 GI:1464250076 8140 694-2517 2459-3931 2922-3689 _______ 1-420 417-707 6000-7673 4580-6154
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Figure 1 -. Comparative representation of CPV genomes. The presence, location and length of each gene are represented. The L2 gene sequence of CPV11, available in GenBank, is mutant, overlapping with the L1 gene sequence.

Figure 1 -

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The infection cycle of CPV follows the differentiation cycle of keratinocytes in the epidermis. Initially, the early genes are expressed in the cell nucleus at the basal layer in which the replication of viral DNA occurs. Then, the expression of early genes reduces and the genome becomes episomal, and there is an increase in the expression of genes that leads to cell cycle control (Yhee et al., 2010; Lange and Favrot, 2011; Lange et al., 2013). The late genes are expressed in the nucleus of the keratinocytes at the stratum spinosum, stratum granulosum and stratum corneum at the end of cell differentiation. The late genes encode the proteins that are responsible for the production of the viral particles and the assembly of the virions into the nucleus. The viral particles are then released (Lange and Favrot, 2011; Lange et al., 2013).

The E1 and E2 genes, which were present in the ancestor of the papillomavirus, act in viral DNA replication in the nucleus of the host cell. The E2 protein is the most regulatory protein in this cycle, facilitating the binding of E1 to the upstream regulatory region (URR or LCR) between L1 and E6 to begin replication (Van Doorslaer et al., 2018).

The genome of all PVs contains the L1 and L2 genes because they are structural and conserved genes, but some early genes are not present in different viral types (Table 1). The observation of specific early genes presence is important because some of these produce oncoproteins such as E5, E6, and E7. Cases of cancer in BPV1 are associated with E5, and in HPV with E6 and E7 (Yuan et al., 2007; Vande Pol and Klingelhutz, 2013). CPV2 and CPV16 have been isolated in cases of cutaneous SCC in dogs, and they produce the oncoproteins E5, E6 and E7. Although all CPV types have the E6 and E7 oncoproteins, more studies should be done to elucidate the role of each CPV type in respect of cancer development risk, and the role of these oncoproteins in the progression of pre-neoplastic lesions to a malignant neoplasia. In this context, to the best of our knowledge, only CPV1, CPV2, CPV3, CPV7, CPV9, CPV12, CPV15, CPV16, and CPV17 have been isolated in cases of cancer (Lange et al., 2016; Thaiwong et al., 2018; Chang et al., 2020b).

The E2 protein may influence the development of cancer in lesions caused by CPV9. Analysis of CPV9 genomes isolated from benign and malignant SCC lesions showed that the nucleotide sequence of the virus from the malignant lesion presents a 328 bp deletion at the 3’end in the gene E2. In cases of cancer due to HPV, E2 deletion results in an increase in E6 and E7 protein expression; however, in a case of SCC due to CPV9 no change in the mRNA expression of E6 and E7 was found, indicating that other mechanisms were responsible, for example, differences in protein translation or stability (Chang et al., 2020b).

Classification and taxonomy

The L1 gene encodes the major viral capsid protein, the L1 protein, which is the main component of the viral particle used for vaccine production. Furthermore, the L1 gene is used for papillomavirus classification and construction of phylogenetic trees (Bernard et al., 2010). Originally, the classification of PVs was based on the similarity between L1 nucleotide sequences. The result of the genetic distance observed from an alignment of multiple sequences and the construction of phylogenetic trees was used to classify the PVs into genus, species, types, subtypes and variants. Different genera share less than 60% identity; different species in the same genus share between 60% and 70% identity; and the identification of a new type occurs when the differences between the nucleotide sequences are greater than 10% compared to the closest known PV type (De Villiers et al., 2004; Van Doorslaer et al., 2017).

In addition to the classification method suggested by De Villiers et al. (2004), which is still accepted, the most recent taxonomy report about the Papillomaviridae family from The International Committee on Taxonomy of Viruses (ICTV) takes into account the visual inspection of phylogenetic trees based on L1, L2, E1 and E2 genes as a genus distinction criterion (Van Doorslaer et al., 2018).

The ICTV is responsible for Papillomaviridae family nomenclature, classifying them into subfamilies, genera and species. The classification criteria for subfamilies also consider the identity of L1 nucleotide sequences, where different members of the subfamilies share less than 45% identity in the L1 gene (Van Doorslaer et al., 2018).

The scientific community adopted the classification of PVs into types, subtypes and variants. The classification of PVs into types is based on the similarity between L1 gene sequences. However, to classify a variant (encompassing the subtype), the complete genome sequences must be analyzed: differences of less than 10% define a new variant; differences of 1% or more between variants of the same type defines the lineages, and differences of 0.5 to 1% define the sublineages (Burk et al., 2013; Chen et al., 2015).

In addition, the nomenclature approved by the ICTV distinguishes two subfamilies: Firstpapillomavirinae and Secondpapillomavirinae. All CPV types belongs to the subfamily Firstpapillomavirinae, and are named based on the Greek alphabet. The species have the same name as the genus plus an Arabic number after the name to differentiate it. The CPV genera and species approved by the ICTV are shown in Table 2.

Table 2 -. CPV genus, species, and types. Species approved by ICTV.

Name Abbreviation Genus Species References
Canis familiaris oral Papillomavirus 1 CPV1 LambdaPV LambdaPV 2 Munday et al., 2016; Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 2 CPV2 TauPV TauPV 1 Munday et al., 2016; Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 3 CPV3 ChiPV ChiPV 1 Munday et al., 2016; Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 4 CPV4 ChiPV ChiPV 2 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 5 CPV5 ChiPV ChiPV 1 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 6 CPV6 LambdaPV LambdaPV 3 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 7 CPV7 TauPV TauPV 1 Munday et al., 2016; Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 8 CPV8 ChiPV ChiPV 3 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 9 CPV9 ChiPV ChiPV 1 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 10 CPV10 ChiPV ChiPV 3 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 11 CPV11 ChiPV ChiPV 1 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 12 CPV12 ChiPV ChiPV 1 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 13 CPV13 TauPV TauPV 2 Munday et al., 2016; Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 14 CPV14 ChiPV ChiPV 3 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 15 CPV15 ChiPV ChiPV 3 Rector and Van Ranst, 2013
Canis familiaris Papillomavirus 16 CPV16 ChiPV ChiPV 2 Munday et al., 2016
Canis familiaris Papillomavirus 17 CPV17 TauPV TauPV 1 Munday et al., 2016
Canis familiaris Papillomavirus 18 CPV18 ChiPV ChiPV 1 Lange et al., 2016
Canis familiaris Papillomavirus 19 CPV19 TauPV TauPV 1 Tisza et al., 2016
Canis familiaris Papillomavirus 20 CPV20 ChiPV ChiPV 1 NCBI
Canis familiaris Papillomavirus 21 CPV21 TauPV - NCBI
Canis familiaris Papillomavirus 22 CPV22 TauPV _ NCBI
Canis familiaris Papillomavirus 23 CPV23 TauPV _ NCBI
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PVs are named according to the scientific name of the host and the type of papillomavirus identified. The canine papillomavirus is therefore named “Canis familiaris Papillomavirus” (CPV) with the identification number of the type added to the end of the name, except in the case of CPV1 which is known as “Canis familiaris oral Papillomavirus” (Bernard et al., 2010). In the database Papillomavirus Episteme (PaVE), the 23 CPV types identified to date are distibuted into three genera: Lambdapapillomavirus (LambdaPV) (CPV 1, 6), Taupapillomavirus (TauPV) (CPV 2, 7, 13, 17, 19, 21, 22, 23) and Chipapillomavirus (ChiPV) (CPV 3-5, 8-12, 14-16, 18, 20) (Figure 2).

Figure 2 -. Midpoint maximum likelihood phylogenetic tree based on L1 nucleotide sequences of CPV. Branch support was assessed with 1000 bootstrap replicates. The evolutionary model of nucleotide substitution was the TVM+I+G, selected by jModelTest. Bar scale represents the nucleotide substitution per site. Each type of CPV is grouped together in genus-based clusters: Taupapillomavirus, Lambdapapillomavirus or Chipapillomavirus.

Figure 2 -

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Genetic diversity and pathogenicity

PV types, subtypes and variants may differ in virulence and influence host disease development (Lange and Favrot, 2011). In dogs, for example, lesions caused by CPV can differ clinically according to the type of PV with which they were infected (Zhou et al., 2014). For comparison purposes, there are more than 220 identified types of HPV in the PaVE database, while, so far, only 23 types of CPV have been identified (Bernard et al., 2010). There is, therefore, a need for more studies focusing on the analysis of CPV genetic diversity.

CPV have been identified worldwide (Sykes and Luff, 2014); Table 3 shows the different CPV types with their associated lesion and the country of origin. HPV studies show that different etiologies, risk factors, and the prevalence of a viral type may be associated with its geographic origin (Sabattini et al., 2016). Information on the geographical distribution of CPVs is still scarce, but more data in this area could contribute to a better understanding of the risk factors related to infection with particular types. As certain types of CPV have been confirmed as risk factors for malignant skin lesions, the risk of cancer development may vary according to the prevalence and geographical distribution of these CPV types.

Table 3 -. Geographical distribution of CPV types and their associated lesions in dogs per country of identification.

Country CPV type Lesions GenBank ID References
Mexico CPV CTVT _______ Ayala-Díaz et al., 2019
Brazil CPV1 Exophytic oral and cutaneous papillomas KF199909 Alcântara et al., 2014
Brazil CPV1 Exophytic oral and cutaneous papillomas; oral SCC in situ MF321769 - MF321777 Reis et al., 2019
Italy CPV1 Oral SCC _____ Porcellato et al., 2014
Italy CPV1 Oral, cutaneous, tonsillar - SCC _____ Sabattini et al., 2016
Italy CPV1 Endophytic papillomas GQ204117 Lange et al., 2010
Korea CPV1 Oral papillomas _____ Yhee et al., 2010
Turkey CPV1 Oral papillomatosis _____ Sancak et al., 2015
Turkey CPV1 Oral e cutaneos papillomatosis KY445587 - KY445599 Oğuzoğlu et al., 2017
Germany CPV1 Oral papillomas, oral SCC _____ Teifke et al., 1998
South Korea CPV1 Oral cancer FJ479789.1 Unpublished
South Africa CPV1 Oral papilloma KX587461.1 Regnard et al., 2016
Switzerland CPV1 Assymptomatic _____ Lange et al., 2011
China CPV1 Oral papilloma HM054515.1 Unpublished
Taiwan CPV1 Oral papilloma MN617831-33 Chang et al., 2020a
Taiwan CPV1 Digital papilloma MN617834 Chang et al., 2020a
USA CPV1 SCC _____ Thaiwong et al., 2018
Taiwan CPV2 Papilloma inthe elbow MN606026 Chang et al., 2020a
Germany CPV2 Endophytic papillomas GQ204118 Lange et al., 2010
USA CPV2 Footpad lesions, endophytic papilloma NC_006564 Yuan et al., 2007
Japan CPV2 Papilloma on footpads LC363559 Iyori et al., 2019
USA CPV3 Pigmented plaques _____ Luff et al., 2012b
Switzerland CPV3 Epidermodysplasia verruciformis, in situ SCC NC_008297 Tobler et al., 2006
USA CPV3 Pigmented plaques, SCC ______ Thaiwong et al., 2018
USA CPV4 Pigmented plaques _____ Luff et al., 2012a
Switzerland CPV4 Pigmented plaques NC_010226 Unpublished
Japan CPV4 Pigmented plaques LC489227-29 Yu et al., 2019
Australia CPV4 Saliva samples MK205376-79 Bhatta et al., 2019
Germany CPV5 Pigmented plaques FJ492743 Lange et al., 2009
USA CPV5 Pigmented plaques _____ Luff et al., 2012b
Switzerland CPV6 Endophytic papillomas GQ204119 Lange et al., 2010
Taiwan CPV6 Digital inverted papilloma MN606027 Chang et al., 2020a
Taiwan CPV6 Papilloma in the paw MN606028 Chang et al., 2020a
Switzerland CPV6 Endophytic papillomas FJ492744 Lange et al., 2009
Scotland CPV7 Exophytic papillomas, SCC FJ492742 Lange et al., 2009
Switzerland CPV8 Pigmented plaques HQ262536 Lange et al., 2012b
Australia CPV8 Saliva sample MK205381 Bhatta et al., 2019
New Zealand CPV9 Pigmented plaques GU220384 ______
USA CPV9 Pigmented plaques JQ040505 Luff et al., 2012b
USA CPV9 Pigmented plaques JF800656 Yuan et al., 2012
Taiwan CPV9 Digital papilloma; inguinal SCC MN606029 Chang et al., 2020a
Taiwan CPV9 Cutaneous papilloma MN606030 Chang et al., 2020a
Japan CPV9 Skin pigmented plaque MT265226 Chang et al., 2020a
Taiwan CPV9 SCC MT265225 Chang et al., 2020a
Switzerland CPV9 Pigmented plaques JQ701801 Lange et al., 2013
USA CPV10 Pigmented plaques JQ040504 Luff et al., 2012b
USA CPV10 Pigmented plaques NC_016075 Luff et al., 2012a
USA CPV11 Pigmented plaques JF800658 Zhou et al., 2014
USA CPV11 Pigmented plaques JQ040501 Luff et al., 2012b
USA CPV12 Pigmented plaques, SCC _____ Luff et al., 2016
USA CPV12 One pigmented plaque JQ754321 Zhou et al., 2015
USA CPV12 Pigmented plaques JQ040502 Luff et al., 2012b
USA CPV12 Footpad lesions KX817182 Anis et al., 2016
Switzerland CPV13 Oral papillomatosis JX141478 Lange et al., 2012a
Switzerland CPV14 Pigmented plaques NC_019852 Lange et al., 2013
USA CPV15 Pigmented plaques JQ040503 Luff et al., 2012b
Taiwan CPV15 Digital verrucous scc MN606031 Chang et al., 2020a
Taiwan CPV16 Inguinal SCC MN606032 Chang et al., 2020a
Taiwan CPV16 Dysplasia of squamous ephiyelium MN606033 Chang et al., 2020a
Taiwan CPV16 SCC MN606034; MN606035 Chang et al., 2020a
USA CPV16 Pigmented plaques, SCC KP099966 Luff et al., 2016
Brazil CPV16 Pigmented plaques; in situ and invasive SCC MG009510 Alves et al., 2020
USA CPV16 Pigmented plaques, SCC ___ Thaiwong et al., 2018
New Zealand CPV17 Oral SCC KT272399 Munday et al., 2016
Australia CPV17 Saliva samples MK205383-91 Bhatta et al., 2019
USA CPV18 Pigmented plaques JQ040499 Luff et al., 2012b
USA CPV18 Pigmented plaques KT326919 Lange et al., 2016
Japan CPV18 Pigmented plaques LC489230-31 Yu et al., 2019
USA CPV19 Oral papilomatosis KX599536 Tisza et al., 2016
USA CPV20 _ KT901797 Unpublished
USA CPV21 Respiratory infection signs MH285952 Altan et al., 2019
USA CPV22 Respiratory infection signs MH285953 Altan et al., 2019
USA CPV23 Respiratory infection signs MH285954 Altan et al., 2019
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The first Canis familiaris oral Papillomavirus 1 (CPV1) was identified in 1994, and remains the most commonly detected type worldwide (Delius et al., 1994; Sancak et al., 2015). Since then, several sequences of CPV1 have been deposited in public databases, which has shown the genome to be highly conserved, which may influence the nature of infection (Regnard et al., 2016). CPV1 is known to cause oral papillomas, but has also been detected in ocular conjunctiva epithelial hyperplastic lesions, cutaneous papillomas and is present in asymptomatic dogs (Brandes et al., 2009; Lange and Favrot, 2011; Lange et al., 2011; Sancak et al., 2015).

Furthermore, other types have been identified in the oral cavity, namely CPV types 2, 4, 8, 13, 17 and 19 (Munday et al., 2016; Tisza et al., 2016; Lange et al., 2019). In the USA, CPV2 and CPV19 were identified together with CPV1 in a case of coinfection of oral papillomatosis (Tisza et al., 2016). Another study demonstrated the coinfection of canine papillomavirus with CPV1 and CPV2 together but in different lesions: cutaneous and eyelid conjunctiva papillomas (Lange et al., 2019). CPV13 and 17 were identified in samples from New Zealand and Switzerland, respectively. CPV4, CPV8 and CPV17 were detected in samples of dog saliva from Australia (Table 3).

Oral papillomatosis is most common in young dogs, and it is manifested by exophytic warts that have a hard consistency with a cauliflower, nodular or fringed form (Lange and Favrot, 2011). This kind of lesion can multiply and persist in immunosuppressed dogs, resulting in the worsening of clinical symptoms and pharyngeal obstruction and dysphagia (Fernandes et al., 2009).

The cutaneous lesions due to CPV infection could be exophytic or endophytic papillomas, which can be differentiated by histopathological examination. CPV types 1, 2, 6, 7, 9 and 12 have been identified in cutaneous papillomas. All these CPV types were related to exophytic papillomas. It should be noted that CPV7 has only been found in cutaneous exophytic lesions associated with malign neoplasia, while CPV9 has only been found in exophytic cutaneous papilloma with generalized verrucosis. Moreover, endophytic papillomas have only been only associated with CPV types 1, 2 and 6 (Lange et al., 2010; Lange and Favrot, 2011; Cavana et al., 2015; Anis et al., 2016; Munday et al., 2016).

CPV2 is characterized by tropism in the footpad region, with the presence of endophytic papillomas, and has been found in dogs from Germany, Japan and the USA. In addition to CPV2, CPV12 was also found in footpad lesions in dogs from the USA, and other CPV types were identified in endophytic papillomas of dogs from different countries: CPV1 in Italy; and CPV6 in Switzerland and Taiwan (Table 3).

Clinically, endophytic lesions have been described as having distinct cutaneous presentations namely classic greyish cup-shaped nodules 1-2 cm in diameter with a central pore, dome-shaped lesions 4mm in diameter, and black papules 2mm in diameter (Lange et al., 2010).

Histologically, the changes found in exophytic lesions are epidermal hyperplasia, hyperkeratosis, inclusion bodies, keratohyalin granules in the spinous layer, clear cells, koilocytes (Lange and Favrot, 2011), hyperplasia of the epithelium, hyperpigmentation, hyperkeratosis and keratohyaline granules occurring in the pigmented plaques (Luff et al., 2016). The endophytic lesions show epidermal papillary projections extending into the dermis. Parakeratotic cells, keratohyaline granules, koilocytes, inclusion bodies intranuclear basophilic and eosinophilic may also occur in endophytic lesions, and eosinophilic cytoplasmic inclusions have also been observed (Lange et al., 2009).

Lambpapillomavirus and Taupillomavirus are involved in endophytic and exophytic lesions. However, the most recently identified types of Taupapillomavirus, CPV 21, 22, 23, were detected in samples from dogs with signs of respiratory infection from metagenomic analysis of the nasal virome (Altan et al., 2019).

Pigmented plaques, another form of disease caused by CPV, are hyperkeratotic, hyperpigmented plaques of up to 3 cm in diameter usually located in the leg and abdomen. All CPV types isolated in benign pigmented viral plaques belongs to the genus ChiPVs (Munday and Kiupel, 2010; Lange et al., 2013).

Pigmented plaques have been described in the USA (CPV 3-5, 9-12, 15, 16, 18), Germany (CPV5), Switzerland (CPV 3, 4, 8, 9, 14), Japan (CPV4, 9, 18), New Zealand (CPV9 and 15), and Brazil (CPV16) (Table 3). CPV18 and CPV4 have been identified in pigmented plaques of Pug dogs, indicating a possible genetic predisposition to the virus (Lange et al., 2016; Yu et al., 2019).

In the pigmented plaques histology, it is possible to observe acanthosis; hyperkeratosis, hyperpigmentation and hyperplasia of the epidermis; clusters of large keratohyaline granules in the spinous stratum; and koilocytes in the stratum granulosum or clear cells (Lange and Favrot, 2011; Lange et al., 2013; Yu et al., 2019).

Studies have shown CPV infection to have a self-limiting characteristic. Oral lesions caused by CPV1 can also be self-limiting over a period of one year (Sancak et al., 2015). In addition, a regression of a footpad exophytic lesion due to CPV2 infection has been observed after biopsy (Iyori et al., 2019).

In Mexico, sequences of CPV DNA were identified in 16 of 21 cases of canine transmissible venereal tumor. This tumor is present in the genital organ as a mass and is sexually transmissible. There is no definition of its etiology and further studies are necessary to determine whether CPV is involved in the development of this type of cancer and which type or variant might be responsible for the disease (Ayala-Díaz et al., 2019).

Cancer - Squamous Cell Carcinoma (SCC)

SCC is a common cancer in dogs, especially oral SCC, which is the second most common neoplasm in the oral cavity of dogs (Munday et al., 2016). However, the etiology of oral SCC in dogs is not yet well established. In humans, for example, about 25% of oral SCC is due to HPV infection (Ryerson et al., 2008). CPV types have been associated with the progression of cutaneous pigmented plaques to SCC (Goldschmidt et al., 2006; Luff et al., 2016). However, some studies have shown that progression is rare and the etiology of canine SCC is still unclear (Porcellato et al., 2014; Munday et al., 2015a; Sabattini et al., 2016).

The development of cutaneous SCC, with the presence of PV antigens detected by immunohistochemistry (IHC), occurred in dog at sites where vaccines of live CPV1 was injected (Bregman et al., 1987). The first report of oral SCC caused by CPV1 was demonstrated by IHC in 1998, with the progression of the lesion in the oral cavity (Teifke et al., 1998). The presence of CPV1 DNA in oral SCC has been demonstrated in other studies, but how the virus acts in the progression to cancer has yet to be determined (Porcellato et al., 2014; Sabattini et al., 2016). Some studies have reported malignant transformation and an increase of CPV1 associated with SCC in the last ten years, suggesting that CPV1 could be responsible for this lesion and its progression to cancer (Ibarra et al., 2018; Thaiwong et al., 2018; Chang et al., 2020a).

Progression to metastatic SCC caused by CPV2 was present in the endophytic lesions of dogs with severe combined immunodeficiency, the result of a mutation in the common gamma chain (Goldschmidt et al., 2006). The progression of multiple pigmented skin plaques into metastatic SCCs was demonstrated in dogs infected with CPV12 and CPV16 (Luff et al., 2016). As occurs in high-risk HPV types, the CPV16 genome has been found to be integrated into the host chromosome in a case of metastatic SCC (Luff et al., 2019).

CPV17 was found in a case of multiple oral SCCs, with increased expression of p16CDKN2A protein (p16). This protein has been used as a molecular marker to demonstrate the etiology of the HPV infection in SCC development (Munday et al., 2015b; Munday et al., 2016). In dogs, the p16 protein has not yet been associated with the etiology of CPV in SCCs, due to the absence of CPV DNA in dogs with this type of cancer and increased expression of p16, and the absence of p16 in some cases of SCC with CPV DNA (Munday et al., 2015a; Sabattini et al., 2016).

Histological examination has shown the malignant transformation of benign lesions due to CPV1, CPV3 and CPV16 infection. Both expression of p53 and p16 was analyzed simultaneously in the same lesions, but both the benign and the malignant lesions had immunoreactivity, making it impossible to identify the same association found in HPV cases, where the immunoreactivity is associated with cancer (Thaiwong et al., 2018). Therefore, further studies are required to identify the mechanisms associated with this progression to cancer. CPV types of all genera have already been identified in cases of SCC: CPV1 (Lambdapapillomavirus); CPV2 (Taupapillomavirus) and CPV 3, 7, 9, 12, 15, 16, 17 (Chipapillommavirus) (Teifke et al., 1998; Goldschmidt et al., 2006; Munday and Kiupel, 2010; Lange and Favrot, 2011; Munday et al., 2015b; Luff et al., 2016; Munday et al., 2016; Thaiwong et al., 2018; Chang et al., 2020a,b).

Studies on HPV have already demonstrated that some specific HPV types are associated with different risks of cancer development, and that some variant lineages are related to increased risk of cervical cancer development when compared to other HPV lineages in different regions of the world. For example, there are some HPV16 and/or HPV18 lineages and sublineages that are associated with an increased risk of cancer (Xi et al., 2007; Bernard et al., 2010; Van Doorslaer, 2013); The HPV16 European variants (lineage A), for example, are associated with less risk of invasive cancer than the HPV16 lineages B, C and D from other parts of the world. On the other hand, non-European HPV18 variants (lineages B and C) seems to be more related to a higher risk of cervical cancer development than European HPV18 variants (lineage A) (Chen et al., 2011; Cullen et al., 2015).

To date, this relationship between the lesions and CPV variants (lineages and sublineages) has been little explored. Some studies have identified different isolates or their DNA sequences which differ from the CPV reference type genome; however, they did not discuss whether these isolates could be CPV variants or not, or their potential role in pathogenesis. For example, different isolates of CPV1 were identified in cases of dogs with oral and cutaneous lesions in Turkey and Brazil (Alcântara et al., 2014; Oğuzoğlu et al., 2017; Reis et al., 2019). In Brazil, samples from different regions of the country have shown variants of CPV1 associated with oral and cutaneous lesions (Alcântara et al., 2014; Reis et al., 2019). In one case of in situ oral SCC in a dog from Brazil, a new CPV1 variant was identified, showing the importance of studies that focus on the discovery of CPV variants that may influence the disease and could be associated with cases of cancer (Reis et al., 2019).

Another factor that is involved in the development of cancer is the expression of the E5, E6 and E7 oncoproteins, which is well known in the HPV infection, but is still unclear in CPV infection. A comparative study with benign and malignant epithelial neoplasia SCC due to CPV9 infection in dogs showed that there is no difference in the mRNA expression of E6 and E7 genes between the benign and malignant lesions. In the same study, it was shown that the E2 protein may influence the development of cancer in lesions caused by CPV9 by the deletion of a nucleotide sequence (Chang et al., 2020b). Therefore, further studies must be carried out to investigate the possible role of CPV proteins involved in cancer development.

Conclusions and future perspectives

Given the fact that HPV in humans is associated with different levels of cancer risk, including a high risk in respect of specific types and variants of HPV, it is reasonable to assume that some types of CPV may also be associated with cancer. A study showing a putative CPV1 variant in a case of oral SCC in situ highlights the importance of the genetic characterization of nucleotide sequences of CPV, identifying the variants that could be more pathogenic and related to cases of cancer around the world.

Studies of CPV genetic diversity are mostly about discovery of new types. However, in order to increase our knowledge in respect of the development of cancer caused by CPV it is important that future studies also focus on the identification and characterization of CPV subtypes and variants, their association with SCC, the expression of genes involved in the progression to cancer, and the epidemiological characteristics of the genetic variants associated with pathogenic aspects.

Acknowledgements

This work was supported in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) [Finance Code 001].

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