Genetic Diversity of the Papillomaviridae Family Using Reference Genomes

Rebeca T. O. Loureiro¹, Michele F. A. Souza², Paulo F. C. Magalhães-Junior³, Suanni L. Andrade¹, Rudi E. L. Procópio^1,2*

¹Graduate Program in Biotechnology and Natural Resources of the Amazon, University of the State of Amazonas (UEA), Manaus, AM, Brazil.
²Graduated Program in Genetics, Conservation, and Evolutionary Biology (PPG GCBEv), National Institute for Amazon Research (INPA), Manaus, AM, Brazil.
³Higher School of Health Sciences, University of the State of Amazonas (UEA), Manaus, AM, Brazil.

DOI: 10.4236/jbm.2025.137014                

Abstract

Papillomaviruses have the ability to induce infected squamous epithelial cells to form tumors, some of which can progress to malignancies. They are circular double-stranded DNA viruses with approximately 8kbp. The papillomavirus genome consists of a long control region (LCR), early coding regions (E1, E2, E4, E5, E6, and E7), and late coding regions (L1 and L2). We used 112 genomic DNA, all of papillomavirus sequences from the NCBI (RefSeq) and listed in the PaVE, comprising 47 human-infecting reference sequences and 65 animal-infecting reference sequences. The main papillomaviruses that infect humans, showed differences in the size of the proteins encoded by the viral genome. For human-infecting papillomaviruses, there was no significant difference between the phylogeny constructed with the E and L regions, compared to the tree constructed with the entire genome. For all genera of the Papillomaviridae family, Betapapillomavirus genera that infect humans were placed between Chipapillomavirus and Taupapillomavirus, in the phylogenetic tree using the entire genome, and showed similarity with Betapapillomaviruses infecting Colobus guereza, which is a species of primate. Human-infecting Alphapapillomaviruses was the most distinct specie among Alphapapillomaviruses, while Gammapapillomaviruses were more closely related to Pipapillomaviruses infecting Mastomys coucha, Micromys minutus, and Mus musculus, which are small rodents.

Keywords

Papilomavirus, Tumors, Neoplasia, Carcinoma, Oncology

1. Introduction

1.1. Genome and Life Cycle

Human Papillomaviruses (HPV) are circular double-stranded DNA viruses, with approximately 8kbp and about 55 nm in diameter, lacking an envelope. Their capsid is composed of 360 molecules of the L1 protein, the main components of the capsid, along with up to 72 copies of the L2 protein, in smaller proportion [1]. They infect the basal layer of the stratified epithelium of the skin and mucous membranes through microlesions, replicating as the cells differentiate [2].

The genomes of Papillomaviridae are conserved, and their eight genes are expressed in a controlled manner within the squamous epithelium. There are six early genes (E1, E2, E4, E5, E6 and E7) and two late genes (L1 and L2), in addition to a long control region (LCR), which acts as a replication origin and controls transcription [3]. The L1 and L2 proteins are produced in the final stage of the virus’s life cycle, and encapsulate the viral DNA [4]. High-risk papillomaviruses have the ability to induce infected squamous epithelial cells to form tumors, some of which may progress to malignancies [5]. Cancer arises due to persistent infections by high-risk HPV that have not been cleared by the host’s immune system. These infections are characterized by dysregulated expression of HPV genes, especially by the high constitutive expression of the virus’s oncogenes E6 and E7 and by the absence of the viral capsid proteins L1 and L2, which are highly immunogenic. HPVs extensively utilize alternative splicing to express their genes, becoming highly dependent on cellular RNA-binding proteins for proper gene expression. The levels of these RNA-binding proteins are altered in precancerous cervical lesions containing HPVs, and in cervical cancer [6]. The E6 and E7 genes of the papillomavirus encode proteins responsible for establishing, and maintaining a cellular environment conducive to the synthesis of the viral genome, and the production of viral progeny in keratinocytes that are in the process of terminal differentiation, and present growth arrest. These E6 and E7 proteins accomplish this role by binding to and functionally reprogramming key cellular regulatory proteins [7]. The viral E6 and E7 genes are consistently expressed in cancers and play a crucial role in tumor initiation, progression and maintenance. E6 and E7 encode small proteins that lack intrinsic enzymatic activities. Instead, they function by binding to cellular regulatory molecules, disrupting normal cellular homeostasis [8]. The viral E6 and E7 proteins drive carcinogenesis by interacting with tumor suppressors and interfering with diverse cellular pathways [9]. Several proteins related to DNA damage response, and interferon modulation, such as BRCA1, H2AX, SIRT1 and LAMP3, are clearly upregulated in primary keratinocytes that express themselves as HPV16 E6 and E7 oncoproteins [10]. Data suggest that the E6 and E7 proteins of β3 HPV49, and α9 HR-HPV16 influence crucial factors in cell cycle control through indirect mechanisms by altering the expression of microRNAs [11]. Regarding the oncogenic proteins expressed during the initial replication cycle of high-risk HPVs, the regulation mechanism of pre-mRNA splicing of E6 and E7 has a significant impact throughout the viral replication cycle. Furthermore, differentiation, control and transformation in HPV-infected immortalized cells are closely linked to the expression levels of E6 and E7 [12]. Innate immune genes (IIGs) are suppressed by HPV16, and this suppression persists until the cancerous stage, indicating that the HPV16 E6 and E7 proteins act synergistically to suppress IIG expression throughout the viral genome [13]. The E6 protein of high-risk HPVs directs several cellular pathways to promote viral DNA replication and is a crucial oncogene in HPV-associated neoplasms, inhibiting p53, suppressing apoptosis, activating telomerase, blocking cell adhesion, polarity, and epithelial differentiation, modifying protein G transcription and signaling, and reducing the immunological recognition of HPV-infected cells [14]. The degradation of p53 is a distinctive feature of human papillomaviruses (HPVs). The E6 oncoprotein forms a ternary complex with the E6 ubiquitin ligase-associated protein E3 (E6AP) and the tumor suppressor protein p53, targeting it for ubiquitination [15].

1.2. Genome Organization and Biological Properties

The E6 and E7 proteins

The viral oncoproteins E6 and E7 play an active role in increasing the intrinsic sensitivity to radiation (radiosensitivity) of infected cells [16]. The enhanced competitive ability of HPV16-infected cells to reach the basal cell surface is primarily attributed to the expression of the E6 oncoprotein, with E7 or E5 oncoproteins not having a significant influence [17]. E6 and E7 induce alterations in the cell cycle, proliferation, invasion, metastasis, and other biological behaviors, influencing tumor-related signaling pathways, which drive the malignant transformation of cells and consequently promote tumorigenesis and cancer progression. E6 and E7 proteins drive tumor formation and development by influencing the activation of various cancer-related signaling pathways, such as the Wnt/β-catenin, PI3K/Akt, and NF-κB pathways [18]. During the viral life cycle of HPV, E7 interferes with the tight linkage between cellular differentiation and proliferation in normal epithelium, allowing viral replication in cells that would normally no longer be in the division phase. This function is directly related to the transformative activities of E7, including tumorigenic initiation and induction of genomic instability [19]. E7 proteins play a fundamental role in the human Papillomavirus life cycle, modifying the cellular environment to favor viral replication. E7 proteins associated with cancer-linked alpha human papillomaviruses, have significant transformative activities, which, along with E6, are crucial, though not sufficient, to induce tumorigenesis in host squamous epithelial cells [20].

The E1 and E2 proteins

The first set of viral proteins, HPV E1 and E2, triggers a DNA damage response and recruits repair proteins to viral replication sites. These proteins are likely co-opted to replicate the viral genome. However, since activation of the DNA damage response (DDR) pathways typically leads to cell cycle arrest, which can disrupt the viral life cycle, the second set of HPV proteins, HPV E6 and E7, prevents the DDR response from halting cell cycle progression or inducing apoptosis [21]. Human Papillomaviruses adjust their replication levels, according to the differentiation status of infected keratinocytes. HPV genomes replicate at low levels in undifferentiated cells but at high levels in differentiated cells. For replication to occur, the viral helicase E1 and the viral transcription/replication activator E2 are required [22]. HPV genome replication is strongly controlled, depending on two viral proteins, E1 and E2. While E1 acts as a DNA helicase, essential for the formation of the genome replication complex, E2 initiates DNA replication and regulates the transcription of viral genes, especially the oncogenes E6 and E7 [6]. E1 encodes the sole HPV enzyme, which is an ATP-dependent DNA helicase that interacts with the cellular DNA replication machinery to replicate the viral genome [23]. It is crucial for the replication and amplification of the viral episome in the nucleus of infected cells. To perform this function, E1 forms a double hexamer at the viral origin, unwinds the DNA at the origin and ahead of the replication fork, and interacts with cellular DNA replication factors [24]. Previous studies have demonstrated that its function is not limited to helicase activity, also involving the recruitment and interaction with other host proteins, potentially driving cell proliferation. Recent research has highlighted the emerging role of HPV E1 protein in cervical carcinogenesis [2]. The E2 proteins of papillomaviruses are crucial for the HPV life cycle, performing well-defined functions in transcriptional regulation, DNA replication initiation, and viral genome partitioning. They are also involved in vegetative DNA replication, post-transcriptional processes, and possibly DNA packaging [25]. In addition to regulating viral gene expression, the HPV E2 protein is essential for the viral replication process [26]. To replicate the viral genome, two viral proteins are essential: E2, which binds to 12-base pair palindromic sequences around the A/T-rich replication origin, and recruits the viral helicase E1 through protein-protein interaction; and E1, which forms a di-hexameric complex that replicates the viral genome in association with host factors [27]. The viral E2 protein plays a fundamental role in episome replication throughout the virus’s life cycle, and its activity is regulated through processes such as phosphorylation, acetylation, SUMOylation, and ubiquitination [28]. The substitution of serine 23 of the E2 protein with alanine disrupts the life cycle of HPV16, impairing its immortalization capability and halting the viral cycle, highlighting the critical importance of this residue in the protein’s function [29]. The viral E1 and E2 proteins of HPV8 play a crucial role in the immune evasion of β-HPV, preventing innate recognition of viral nucleic acids. This mechanism may be essential for establishing persistent β-HPV infections [30]. Variants of E1, E2, and E4 are primarily involved in integration, replication, and viral transcription, while E6 and E7 act as oncoproteins, driving cancer progression. The E5 protein, in turn, regulates cell proliferation and apoptosis, as well as facilitating the activity of E6 and E7 [31].

The E4 and E5 proteins

The E5 proteins are small transmembrane proteins encoded by many papillomaviruses in animals and humans. These proteins have been shown to possess transforming activity in cultured animal cells and presumably also play a role in the viral life cycle. It is believed that E5 proteins modify the activity of cellular proteins [32]. Although E5 is found in high-risk alpha-HPVs that infect mucosal tissues, it is absent in the genomes of high-risk beta-HPVs that affect cutaneous tissues, and are related to skin cancers. This observation raises questions about the role of E5 in papillomavirus-associated pathogenesis. The presence of E5 in some papillomaviruses (high-risk alpha-HPVs affecting mucosal tissues), and its absence in others (high-risk beta-HPVs affecting the skin; such as MmuPV1) has led to doubts about its role in papillomavirus-induced pathogenesis. These findings provide evidence that E5 acts as a co-carcinogen in papillomavirus-induced development [33]. Several studies have indicated that the HPV oncoprotein E5 has the ability to disrupt the normal cell cycle of HPV-infected cells by targeting certain crucial cellular signaling pathways, such as the epidermal growth factor receptor (EGFR) signaling pathway [34]. Over time, the oncoprotein E5 is becoming increasingly recognized, as the third transforming protein of Human Papillomavirus (HPV). Extensive cell proliferation is a distinctive feature of cancer development, and E5 is capable of promoting the proliferation of keratinocytes by positively regulating the epidermal growth factor receptor (EGFR) signaling pathway. Therefore, E5 is believed to indirectly contribute to the completion of the viral life cycle by creating the appropriate cellular environment. By increasing EGFR signaling, E5 delays differentiation and allows for the hyperproliferation of keratinocytes, which would otherwise follow a normal differentiation pathway [35]. Other studies have indicated the importance of HPV16 E5 protein in the late stages of the differentiation-dependent life cycle. It has been observed that organotypic cultures containing HPV16 genomes without E5 showed reduced markers of terminal differentiation compared to cultures containing wild-type HPV16. Additionally, levels and activation of the epidermal growth factor receptor (EGFR) were increased in an E5-dependent manner in these tissues, and EGFR promoted terminal differentiation and expression of the HPV16 L1 gene. These results suggest that E5 plays a role in preserving the differentiation capacity of keratinocytes containing HPV16, thereby facilitating the production of new virus progeny [36]. When E5 is lost during viral integration, its absence indicates a transition from benign lesions to malignant establishment [37]. E5 acts as a potent negative regulator of type I antiviral IFN response pathways and immunoproteasome expression and function, resulting in a reduction in the repertoire of presented peptides. Additionally, it has been observed that E5 directly binds to and blocks the mitochondrial antiviral signaling protein (MAVS) and stimulator of interferon genes (STING), leading to compromised antitumor immunity and decreased immunotherapeutic activity. This allows infected cancer cells to evade host immune surveillance, and resist the effectiveness of immunotherapies [38]. Furthermore, HPV16 genomes without E5 have been observed to have a higher tendency to integrate into the culture over time compared to the wild type, suggesting that E5-mediated suppression of IFN-κ may be crucial for the long-term maintenance of viral genomes, thus revealing a new function of E5 in the viral life cycle [39]. After infection, HPV viral DNA can remain latent and infectious in affected basal epithelial cells, potentially progressing to productive neoplastic infection. This process can lead to transformation over several years, culminating in invasive cancer [40]. The ability of E4 to induce disorders in keratin structure indicates its possible influence on viral release. Although the precise role of E4 in the viral replication cycle remains uncertain, there are suggestions that it may play a significant role in cell cycle disruption. Studies have demonstrated a correlation between E4 expression and levels of HPV DNA incorporation by the host [41]. The expression of HPV16 E4 and E5 proteins, has been shown to cause significant changes in the composition of the cell membrane and the extracellular environment. These alterations are linked to modifications in cell adhesion and differentiation [42]. In HPV infection, the E4 protein is initially produced as an E1^E4 fusion from spliced E1^E4 transcripts, resulting in the first amino acids of the E4 protein being derived from the N-terminal end of E1 [43]. The E4 protein, a phosphoprotein with low molecular weight (10 to 20 kDa), is expressed from a processed E1∧E4 mRNA, whose transcription is initiated from the differentiation-dependent promoter. Expression of the papillomavirus E4 protein is associated with the onset of viral DNA amplification [44]. E4 proteins from various papillomaviruses interact with the serine-arginine-specific protein kinase SRPK1, an important kinase in the replication cycles of various DNA and RNA viruses. E4 inhibits the phosphorylation of SRPK1, not only of cellular SR proteins involved in the regulation of alternative RNA splicing, but also of the viral transcription/replication regulator E2, by regulating late viral gene expression through the inhibition of a host cell kinase [43].

Capsid proteins (L1 and L2)

L1 is the major capsid protein, with molecular weight of approximately 55 kDa, which has the ability to spontaneously self-assemble into virus-like particles (VLPs) after binding to cells. Upon binding, L1 must become flexible enough again to allow the release of the viral genome into a new target cell [45]. Its recombinant expression in various systems leads to self-assembly into empty capsids (VLPs). L1 and L2 are expressed in the granular layer of the epithelium but are not detectable in the basal epithelium that harbors infection [3]. L1 can activate the immune system to generate neutralizing antibodies, which help prevent HPV infections [46]. It has been used as the basis for human papillomavirus (HPV) vaccines [45]. The L2 protein, approximately 500 amino acids in length with an estimated molecular mass of 55 kDa, plays multiple roles in viral genome assembly, encapsidation, and the infectious process. While the L1 protein constitutes the majority of the capsid and can form VLPs, L2 is a smaller component and cannot form VLPs on its own [47]. L2 is tasked with ensuring nuclear delivery of the viral DNA during HPV infection, displacing viral DNA from degradative endolysosomal compartments and directing it to the trans-Golgi network. L2 accomplishes this through the characteristics of an “inducible transmembrane” protein, allowing it to enter into and traverse local vesicular membranes via a transmembrane-like domain [48].

2. Materials and Methods

Genetic Diversity

The Papilloma Virus Episteme (PaVE) has been established to provide highly organized and curated papillomavirus genomic information and tools to the scientific community (https://pave.niaid.nih.gov/). PaVE is an important database that provides access to uniformly curated reference genomes [49]. For the analysis, 112 genomic DNA sequences were used, all of which are reference Papillomavirus sequences in the NCBI RefSeq listed on PaVE, accessed in May 2024. There were 47 curated reference sequences of human papillomaviruses (Table 1) and 65 curated reference sequences of papillomaviruses that infect animals (Table 2), as listed in the curated PaVE database. The NCBI Reference Sequence (RefSeq) is a collection of taxonomically diverse, non-redundant, and richly annotated sequences, the RefSeq collection provides redundancy-free genome data, is used internationally as a standard for genomic annotation, and represents significant taxonomic diversity [50]. Therefore, only the reference genome was chosen. For alignment and phylogeny construction, MEGA allows from DNA sequences, to infer evolutionary trees, estimate distances, genetic diversity, and infer ancestral sequences, MEGA 11 was used [51]. Constructing a multiple alignment corresponds to developing a hypothesis of how a series of sequences have changed over time. The multiple alignment of a series of homologous DNA sequences is the first step toward a phylogeny and was performed using MEGA 11 (by ClustalW). Phylogenetic trees aim to establish similarity among organisms based on their DNA sequence, assisting in forming closely related groups with common characteristics. This was done using MEGA 11 (Neighbor Joining (NJ) Tree, the NJ method is a simplified version of the minimum evolution (ME) method, which uses distance measures to correct for multiple hits at the same sites, and chooses a topology showing the smallest value of the sum of all branches as an estimate of the correct tree).

Table 1. Papillomaviruses that infect humans, listed in the PAVE as reference genomes in the NCBI database.

ID	Species Name	NCBI Refseq	PUBMED Reference
A-4	Alphapapillomavirus 4	NC_001352	1964523 [56]
G-1	Gammapapillomavirus 1	NC_001457	8389082 [57]
A-8	Alphapapillomavirus 8	NC_001595	8205838 [58]
B-2	Betapapillomavirus 2	NC_001596	8205838 [58]
A-2	Alphapapillomavirus 2	NC_001576	8205838 [58]
A-5	Alphapapillomavirus 5	NC_001583	8205838 [58]
A-1	Alphapapillomavirus 1	NC_001586	8205838 [58]
A-11	Alphapapillomavirus 11	NC_001587	8205838 [58]
N-1	Nupapillomavirus 1	NC_001354	1645904 [59]
G-2	Gammapapillomavirus 2	NC_001690	1645904 [60]
B-3	Betapapillomavirus 3	NC_001591	8205838 [58]
G-3	Gammapapillomavirus 3	NC_001691	[61]
A-6	Alphapapillomavirus 6	NC_001593	8205838 [58]
A-13	Alphapapillomavirus 13	NC_001676	Delius, Unpublished
G-4	Gammapapillomavirus 4	NC_001693	1326820 [62]
A-3	Alphapapillomavirus 3	NC_001694	Delius, Unpublished
M-2	Mupapillomavirus 2	NC_001458	8389082 [57]
G-5	Gammapapillomavirus 5	NC_010329	17935140 [63]
A-14	Alphapapillomavirus 14	NC_004104	12085327 [64]
B-4	Betapapillomavirus 4	NC_004500	12919731 [65]
B-5	Betapapillomavirus 5	NC_005134	17412976 [66]
G-6	Gammapapillomavirus 6	NC_008189	17125811 [67]
G-6	Gammapapillomavirus 6	NC_008188	17125811 [67]
G-6	Gammapapillomavirus 6	NC_012213	19153227 [68]
G-7	Gammapapillomavirus 7	NC_012485	19969321 [69]
G-8	Gammapapillomavirus 8	NC_012486	19969321 [69]
G-9	Gammapapillomavirus 9	NC_013035	19570953 [70]
G-10	Gammapapillomavirus 10	NC_014185	20206957 [52]
G-11	Gammapapillomavirus 11	NC_016157	22056388 [71]
G-12	Gammapapillomavirus 12	NC_014469	20542254 [72]
G-13	Gammapapillomavirus 13	NC_014952	21471318 [73]
G-9	Gammapapillomavirus 9	NC_014953	21471318 [73]
G-14	Gammapapillomavirus 14	NC_014954	21471318 [73]
G-12	Gammapapillomavirus 12	NC_014955	21471318 [73]
G-7	Gammapapillomavirus 7	NC_014956	21471318 [73]
G-15	Gammapapillomavirus 15	NC_017993	21844305 [74]
G-11	Gammapapillomavirus 11	NC_017994	21844305 [74]
G-16	Gammapapillomavirus 16	NC_017995	21844305 [74]
G-11	Gammapapillomavirus 11	NC_017996	21844305 [74]
G-17	Gammapapillomavirus 17	NC_017997	21844305 [74]
G-11	Gammapapillomavirus 11	NC_021483	24551244 [75]
G-19	Gammapapillomavirus 19	NC_019023	23043169 [76]
G-21	Gammapapillomavirus 21	NC_022892	24155922 [77]
G-24	Gammapapillomavirus 24	NC_023891	24855297 [78]
G-15	Gammapapillomavirus 15	NC_022095	Kocjan et al., Unpublished
G-27	Gammapapillomavirus 27	NC_027528	26318260 [79]
G-?	Gammapapillomavirus	NC_027779	Arroyo et al., Unpublished

Table 2. Papillomaviruses that infect animals, listed in the PAVE as reference genomes in the NCBI database.

Species Name	Host	NCBI Refseq	PUBMED Reference
Deltapapillomavirus 1	Alces alces	NC_001524	3034730 [80]
Xipapillomavirus 1	Bos taurus	NC_004197	12208979 [81]
Epsilonpapillomavirus 1	Bos taurus	NC_004195	12208979 [81]
Dyoxipapillomavirus 1	Bos taurus	NC_007612	17554025 [82]
Dyolambdapapillomavirus 1	Bettongia penicillata	NC_014143	20200246 [83]
Lambdapapillomavirus 2	Canis familiaris	NC_001619	21552821 [84]
Taupapillomavirus 1	Canis familiaris	NC_006564	17034826 [85]
Chipapillomavirus 1	Canis familiaris	NC_008297	17098970 [86]
Chipapillomavirus 2	Canis familiaris	NC_010226	Tobler et al., Unpublished
Lambdapapillomavirus 3	Canis familiaris	NC_013237	19656968 [87]
Chipapillomavirus 3	Canis familiaris	NC_016014	21883544 [88]
Chipapillomavirus 1	Canis familiaris	NC_016074	22532532 [89]
Chipapillomavirus 3	Canis familiaris	NC_016075	Yuan et al., Unpublished
Chipapillomavirus 3	Canis familiaris	NC_019852	23123172 [90]
Chipapillomavirus 2	Canis familiaris	NC_026640	Luff et al., Unpublished
Deltapapillomavirus 5	Capreolus capreolus	NC_011051	[91]
Dyosigmapapillomavirus 1	Castor canadensis	NC_023178	24309404 [92]
Lambdapapillomavirus 5	Crocuta crocuta	NC_018575	23405364 [93]
Deltapapillomavirus 6	Camelus dromedarius	NC_015267	21471319 [94]
Deltapapillomavirus 6	Camelus dromedarius	NC_015268	21471319 [94]
Betapapillomavirus 1	Colobus guereza	NC_015692	20921322 [95]
Phipapillomavirus 1	Capra hircus	NC_008032	16430985 [96]
Dyochipapillomavirus 1	Equus asinus	NC_023882	24636161 [97]
Zetapapillomavirus 1	Equus ferus caballus	NC_003748	15485669 [98]
Dyoiotapapillomavirus 1	Equus ferus caballus	NC_012123	Scase, Unpublished
Sigmapapillomavirus 1	Erethizon dorsatum	NC_006951	15629787 [99]
Dyoetapapillomavirus 1	Erinaceus europaeus	NC_011765	19218207 [100]
Lambdapapillomavirus 4	Enhydra lutris	NC_023873	Ng et al., Unpublished
Etapapillomavirus 1	Fringilla coelebs	NC_004068	12208979 [81]
Lambdapapillomavirus 1	Felis domesticus	NC_004765	Tachezy et al., Unpublished
Taupapillomavirus 3	Felis domesticus	NC_021472	23639476 [101]
Taupapillomavirus 3	Felis domesticus	NC_022373	Dunowska et al., Unpublished
Treiszetapapillomavirus	Fulmarus glacialis	NC_024300	Gaynor et al., Unpublished
Dyoepsilonpapillomavirus 1	Francolinus leucoscepus	NC_013117	19553340 [102]
Pipapillomavirus 2	Mastomys coucha	NC_008519	Nafz et al., Unpublished
Alphapapillomavirus 12	Macaca fascicularis	NC_012652	19716580 [103]
Alphapapillomavirus 12	Macacca mulata	NC_001678	8396814 [104]
Pipapillomavirus 2	Micromys minutus	NC_008582	17412977 [105]
Pipapillomavirus 2	Mus musculus	NC_014326	21084500 [106]
Iotapapillomavirus 1	Mastomys natalensis	NC_001605	8291235 [107]
Taupapillomavirus	Mustela putorius	NC_022253	23977082 [108]
Dyomupapillomavirus 1	Morelia spilota	NC_016013	21910860 [109]
Deltapapillomavirus 3	Ovis aries	NC_001789	Karlis et al., Unpublished
Kappapapillomavirus 1	Oryctolagus cuniculus	NC_002232	10753723 [110]
Deltapapillomavirus 2	Odocoileus virginianus	NC_001523	2993669 [111]
Treisepsilonpapillomavirus 1	Pygoscelis adeliae	NC_023894	24686913 [112]
Thetapapillomavirus 1	Psittacus erithacus	NC_003973	12110158 [113]
Alphapapillomavirus 12	Papio hamadryas	NC_017716	22446324 [114]
Lambdapapillomavirus 4	Procyon lotor	NC_007150	15958682 [115]
Omikronpapillomavirus 1	Phocoena spinipinnis	NC_003348	17554024 [116]
Psipapillomavirus 1	Rousettus aegyptiacus	NC_008298	16854536 [117]
Dyokappapapillomavirus 2	Rupicapra rupicapra	NC_023895	24910075 [118]
Xipapillomavirus 3	Rangifer tarandus	NC_021930	23874987 [119]
Kappapapillomavirus 2	Sylvilagus floridanus	NC_001541	2984661 [120]
Dyodeltapapillomavirus 1	Sus scrofa	NC_011280	18796716 [121]
Dyoomikronpapillomavirus 1	Saimiri sciureus	NC_023496	Chen et al., Unpublished
Rhopapillomavirus 1	Trichechus manatus	NC_006563	15507660 [122]
Rhopapillomavirus 1	Trichechus manatus	NC_016898	Wellehan, Unpublished
Upsilonpapillomavirus 1	Tursiops truncatus	NC_011109	18579177 [123]
Upsilonpapillomavirus 2	Tursiops truncatus	NC_008184	17098971 [124]
Omegapapillomavirus 1	Ursus maritimus	NC_010739	18215475 [125]
Dyonupapillomavirus 1	Zalophus californianus	NC_015325	Hoffman et al., Unpublished

3. Results and Discussion

In the Papillomaviridae family, there are currently 29 genera, named according to the Greek alphabet from alpha to omega. The term “Dyo” was added for extra genera. After the exhaustion of the Greek alphabet, the classification of papillomavirus types is based on the DNA sequence of the L1 gene. Papillomavirus types within a species share between 71% and 89% nucleotide identity within the complete L1 ORF, and members of the same genus share > 60% nucleotide sequence identity in the L1 ORF [52]. The main papillomaviruses that infect humans (alpha, beta, and gamma) present differences in the size of the proteins encoded by the viral genome: E6 142aa, E7 104aa, E1 642aa, E2 394 aa, E5 42aa, L2 476aa and L1 503aa for Alphapapillomavirus (NC_001586); E6 148aa, E7 93aa, E1 605aa, E2 461aa, L2 533aa and L1 507aa for Betapapillomavirus (NC_001596); and E6 140aa, E7 100aa, E1 599aa, E2 402aa, L2 521aa and L1 516aa for Gammapapillomavirus (NC_001457), as shown in Figure 1. The structure prediction of the proteins shown in Figure 1 was performed for Alphapapillomavirus (NC_001586), using Galaxy (Galaxy TBM) [53]. Human papillomaviruses are the most studied and are distributed in give genera (Alpha, Beta, Gamma, Mu, and Nu) [54]. According to the phylogenetic trees, there was no significant difference between the phylogeny formed with the E region (Figure 2(B)) and L region (Figure 2(C)) in comparison to the tree formed with the entire genome (Figure 2(A)). Gamma-papillomavirus is more related to Betapapillomavirus than to Alphapapillomavirus in all three phylogenetic trees (Figure 2). The two papillomaviruses Mupapillomavirus and Nupapillomavirus are grouped together in the tree based on the genome (Figure 2(A)) and for the L region (Figure 2(C)), whereas for the E region, Nupapillomavirus appeared to be the most distinctive virus (Figure 2(B)). The papillomavirus with the highest number of species and reference genomes is Gammapapillomavirus. Species 2, 3, 12, and 14, as well as 9, 11 and 16, remain grouped in all three trees. Species 6 and 7 remain grouped in the E and L regions, but when the entire genome is used, they are not closely related. The same occurs for 5, 8 and G, which is an unclassified papillomavirus. Within the genus Alphapapillomavirus, species 2, 3, 4, and 14 showed almost the same phylogenetic associations obtained with E, L, and the genome. In Betapapillomavirus, the grouping of L was different (5, 4, 2, and 3), while in using the E region and the genome, the same arrangement was maintained in the phylogenetic trees (5, 4, 3, and 2). Comparative analysis of the trees generated by the genome revealed almost the same phylogenetic associations as obtained by the E and L regions. For all genera of the Papillomaviridae family, the human-infecting Betapapillomavirus was positioned between Chipapillomavirus and Taupapillomavirus in the phylogenetic tree using the entire genome (Figure 3), and showed similarity to the Betapapillomavirus infecting Colobus guereza, which is a species of primate. The human-infecting Alphapapillomavirus was the most distinctive species among the Alphapapillomavirus. The genus Alphapapillomavirus is the most extensively studied of all genera. According to the PAVE database, there are currently 82 types of Alpha-PVs, classified into 14 species [54]. Phylogenetic analysis revealed that Dyonupapillomavirus, which infects Zalophus californianus (California sea lion), is more closely related to the genus Alphapapillomavirus. According to the phylogenetic tree (Figure 3), Gammapapillomavirus is close to Pipapillomavirus, which infects Mastomys coucha, Micromys minutus, and Mus musculus (small rodents). The phylogenetic tree inferred from genomic DNA sequences (Figure 3) showed that Epsilonpapillomavirus, which infects Bos taurus, falls within the clade of Deltapapillomavirus, which exhibits high diversity and infects various domestic animals such as Ovis aries, Bos taurus, and Camelus dromedarius. The two main domestic animals, dogs (Canis familiaris) and cats (Felis catus), are infected by several genera that have been classified into two groups. Group I contains Chipapillomavirus, which has been identified only in dogs so far. Group II comprises genera that infect large domestic animals such as Bos taurus, Camelus dromedarius, and Equus ferus, with the main genus being Deltapapillomavirus. Cattle and dogs can be infected by three different genera. Bos taurus can be infected by Xipapillomavirus, Epsilonpapillomavirus, and Dyoxipapillomavirus, while Canis familiaris can be infected by Lambdapapillomavirus, Taupapillomavirus, and Chipapillomavirus. Papillomaviruses have been discovered in a wide variety of vertebrates, comprising a diverse group of viruses that infect humans and animals. The L1 gene was chosen from the beginning as the standard for classification, since for some types of papillomaviruses, there is little sequence information outside of this region. To be classified as distinct types, individual papillomaviruses must be at least 10% divergent from each other in their L1 nucleotide sequences. Overall, sequence-based phylogeny provides some useful insights into disease associations, although closely related types may, in some cases, present distinct pathologies. It is evident that viral pathogenicity depends on multiple factors, including viral genotype, the nature of the infected cell (tropism), and the host’s immune status [55].

Figure 1. Proteins encoded by genes of Alphapapillomavirus 1 (NC_001586). Genome map of Alphapapillomavirus 1 (NC_001586), Betapapillomavirus 2 (NC_001596), and Gammapapillomavirus 1 (NC_001457). Showing the differences (number of amino acids—aa) in the size of the main structures of the three genera.

Figure 2. Phylogenetic tree of human papillomavirus: A) whole genome, B) E region (E6 to E2), and C) L region (L1 and L2). Showing the relationship between the Alphapapillomavirus (α), Betapapillomavirus (β), and Gammapapillomavirus (γ). Several species tend to maintain the same topology within the trees, regardless of whether they use the entire genome, or use only the L region and the E region, as in the example of species 2, 3, 12 and 14 of the Gammapapillomavirus. Numbers at the nodes indicate bootstrap support (percentage of 500 bootstrap replications). Scale bars represent 10% nucleotide substitution.

Figure 3. Phylogenetic tree of papillomaviruses that infect animals, together with Alphapapillomavirus 1, Betapapillomavirus 2 and Gammapapillomavirus 1 that infect humans (highlighted in blue). Showing the relationship of these three, with the other papillomaviruses. Numbers on nodes indicate the bootstrap support (500 bootstrap replication percentage). Scale bars represent 10% nucleotide substitution.

4. Conclusion

There is a difference in the number of amino acids in the main structures (E and L) between Alphapapillomavirus, Betapapillomavirus and Gammapapillomavirus. There was no difference between the phylogeny constructed with the E and L regions when compared with the tree constructed with the entire genome; both trees presented very similar topologies. The viruses that infect humans (Alphapapillomavirus, Betapapillomavirus and Gammapapillomavirus) were distributed along the phylogenetic tree, containing the viruses that infect animals, Gammapapillomavirus was close to Pipapillomavirus, Betapapillomavirus was between Chipapillomavirus and Taupapillomavirus.

Funding Information

This work was supported by Fundação de Amparo a Pesquisa do Estado do Amazonas (FAPEAM).

Conflicts of Interest

The authors declare no conflicts of interest.

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