Abstract
HPV204 is the only newly identified Mupapillomavirus (Mu-PV) type in more than a decade. To comprehensively characterize HPV204, we performed a detailed molecular analysis of the viral genome and evaluated its clinical relevance in comparison to the other Mu-PVs, HPV1 and HPV63. The 7,227-bp long genome of HPV204 exhibits typical genomic organization of Mu-PVs with eight open reading frames (ORFs) (E6, E7, E1, E2, E8, E4, L2, and L1). We developed three type-specific quantitative real-time PCRs and used them to test a representative collection (n = 1,006) of various HPV-associated benign and malignant neoplasms, as well as samples of clinically normal cutaneous, mucosal, and mucocutaneous origins. HPV204, HPV1, and HPV63 were detected in 1.1%, 2.7%, and 1.9% of samples tested, respectively, and were present in skin and mucosa, suggesting dual tissue tropism of all Mu-PVs. To evaluate the etiological role of Mu-PVs in the development of HPV-associated neoplasms, Mu-PV viral loads per single cell were estimated. HPV1 and HPV63 were present in high viral copy numbers in 3/43 and 1/43 cutaneous warts, respectively, and were identified as the most likely causative agents of these warts. HPV204 viral load was extremely low in a single HPV204-positive cutaneous wart (7.4 × 10−7 viral copies/cell). Hence, etiological association between HPV204 and the development of cutaneous warts could not be established. To the best of our knowledge, this is the first study to evaluate the genetic variability of Mu-PVs by sequencing complete LCR genomic regions of HPV204, HPV1, and HPV63. We detected several nucleotide substitutions and deletions within the LCR genomic regions of Mu-PVs and identified two genetic variants of HPV204 and HPV63 and five genetic variants of HPV1.
Highlights
Human papillomaviruses (HPVs) are small, double-stranded and highly diverse DNA viruses of the Papillomaviridae family, which typically infect human epithelial cells [1]
To determine the tissue tropism and potential clinical significance of MuPVs, we systematically investigated the prevalence of HPV204, HPV1, and HPV63 and determined corresponding viral loads in Mu-PV–positive samples in a representative collection of clinical specimens commonly associated with HPV infection, using three newly developed quantitative type-specific real-time PCRs (RT-PCRs)
To identify potential single nucleotide polymorphism (SNP) and/or deletions, complete long control region (LCR) genomic regions were subsequently aligned with HPV204, HPV1, and HPV63 reference sequences obtained from the Papillomavirus Episteme (PaVE), and with all other available Mu-PV sequences in the Genbank database (Genbank accession numbers NC_001356 and U06714, both HPV1)
Summary
Human papillomaviruses (HPVs) are small, double-stranded and highly diverse DNA viruses of the Papillomaviridae family, which typically infect human epithelial cells [1]. Based on the identity of the complete L1 gene nucleotide sequences, HPVs are hierarchically classified into genera, species, and types. In 1980, HPV1 was isolated and cloned from tissue specimens of deep plantar warts [7, 8] and its complete nucleotide sequence was obtained 2 years later (GeneBank accession numbers V01116 and NC_001356) [9]. Nucleotide sequence (GeneBank accession number KP769769) of the complete viral genome was submitted to the HPV Reference Center at the Karolinska Institute. According to the International Committee on Taxonomy of Viruses (ICTV), HPV204 constitutes a distinct species (Mu-3) within the Mu-PV genus, since the L1 nucleotide sequence of HPV204 exhibits only 66.3% and 66.7% sequence identity with L1 genes of HPV1 and HPV63, respectively (https://talk.ictvonline.org/files/ictv_official_taxonomy_updates_ since_the_8th_report/m/animal-dna-viruses-and-retroviruses?pi4565=2). To the best of our knowledge, this is the first study to assess genetic diversity of Mu-PVs by amplifying and sequencing their complete LCR genomic regions
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