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Background The number of members in the genus Gammapapillomavirus of Family Papillomaviridae has recently been expanding most rapidly. The aim of this study was to characterize a novel human gammapapillomavirus type identified in a vaginal swab from a 25-year-old pregnant woman suffering from vaginitis. Methods Viral metagenomics method was used to detect the viral sequences in 88 vaginal swab samples collected from 88 pregnant women with vaginitis. A novel papillomavirus, named HPV-ZJ01 (GenBank no. KX082661), was detected in one sample and its complete genome sequence was amplified by PCR and sequenced by Sanger walking. Phylogenetic analyses based on the complete genome and the L1 protein of HPV-ZJ01 and other representative human papillomaviruses were done, respectively. Further PCR screening was performed in vaginal swabs (n = 135), cervical smears (n = 40) and cervical cancer tissues (n = 40) using nested-PCR primers designed based on HPV-ZJ01 sequence to investigate the prevalence of HPV-ZJ01. Results The genome of HPV-ZJ01 is 7,358 bp in length with a GC content of 37.8 %. HPV-ZJ01 was predicted to contain six open reading frames (E6, E7, E1, E2, L2, and L1) and a non-coding long control region (LCR). The genome shared the highest overall similarity to HPV-166, with 70.6 % nucleotide sequence identity while its L1 gene shared the highest nucleotide similarity to HPV-162, with 71.1 % sequence identity. Phylogenetic analysis suggested that HPV-ZJ01 belongs to a novel HPV type in the Gamma-PV genus, species Gamma-19, already containing HPV161, HPV162 and HPV166. PCR screening results indicated that none of the other samples were positive for HPV-ZJ01 except the original HPV-ZJ01 positive vaginal swab specimen. Conclusion The genome sequence of a novel type of species Gamma-19 HPV was characterized. The screening PCR results suggested that HPV-ZJ01 is not associated with any of the cervical cancer samples tested. In order to confirm the prevalence and disease association, if any, for HPV-ZJ01, a further study with different sample types and a larger sample size is needed.

To determine the prevalence, viral load, tissue tropism, and genetic variability of novel human papillomavirus (HPV) type 179, which is etiologically associated with sporadic cases of common warts in immunocompromised patients, and phylogenetically related HPV types 135 and 146. The representative collection of 850 HPV-associated clinical samples (oral/nasopharyngeal/anal, archival specimens of oral/oropharyngeal/conjunctival/cervical/skin cancer, benign lesions of the larynx/conjunctiva/skin, and eyebrows), obtained from immunocompetent individuals, was tested for the presence of HPV179, HPV135, and HPV146 using type-specific real-time PCRs. To assess the genetic diversity of the HPVs investigated in the non-coding long control region (LCR), several highly sensitive nested PCR protocols were developed for each HPV type. The genetic diversity of HPV179 was additionally determined in 12 HPV179 isolates from different anatomical sites of an only immunocompromised patient included in the study. HPV179, HPV135, and HPV146 were detected in 1.4, 2.0, and 1.5% of the samples tested, respectively, with no preference for cutaneous or mucosal epithelial cells. One (with five single nucleotide polymorphisms; SNPs), four (with one to six SNPs), and four (with one to eight SNPs) genetic variants of HPV179, HPV135, and HPV146, respectively, were identified among eligible samples. HPV179 isolates from the immunocompromised patient exhibited the identical LCR nucleotide sequence, suggesting that HPV179 can cause generalized HPV infections. HPV179, HPV135, and HPV146 have a mucocutaneous tissue tropism and are associated with sporadic infections in immunocompromised and immunocompetent individuals. Because the majority of mutations were found outside the major functional domains of the respective LCRs, we assume that HPV179, HPV135, and HPV146 genetic variants pathogenically do not differ from their prototypes. In addition, no association was found between specific HPV179, HPV135, and HPV146 genetic variants and anatomical sites of infection and/or specific neoplasms.

It is becoming clear that, in addition to gene gain, the loss of genes may be an important evolutionary mechanism for many organisms. However, gene loss is often associated with an increased mutation rate, thus quickly erasing evidence from the genome. The analysis of evolutionarily related sequences can provide empirical evidence for gene loss events. This paper analyzes the sequences of over 300 genetically distinct papillomaviruses and provides evidence for a role of gene loss during the evolution of certain papillomavirus genomes. Phylogenetic analysis suggests that the viral E6 gene was lost at least twice. Despite belonging to distant papillomaviral genera, these viruses lacking a canonical E6 protein may potentially encode a highly hydrophobic protein from an overlapping open reading frame, which we designate E10. Evolutionary pressure working on this alternative frame, may explain why, despite having lost the E6 open reading frame between 20 and 60 million years ago, evidence of an E6-like protein is conserved.

The novel human papillomavirus type 199 (HPV199) was initially identified in a nasopharyngeal swab sample obtained from a 25 year-old immunocompetent male. The complete genome of HPV199 is 7,184 bp in length with a GC content of 36.5%. Comparative genomic characterization of HPV199 and its closest relatives showed the classical genomic organization of Gammapapillomaviruses (Gamma-PVs). HPV199 has seven major open reading frames (ORFs), encoding five early (E1, E2, E4, E6, and E7) and two late (L1 and L2) proteins, while lacking the E5 ORF. The long control region (LCR) of 513 bp is located between the L1 and E6 ORFs. Phylogenetic analysis additionally confirmed that HPV-199 clusters into the Gamma-PV genus, species Gamma-12, additionally containing HPV127, HV132, HPV148, HPV165, and three putative HPV types: KC5, CG2 and CG3. HPV199 is most closely related to HPV127 (nucleotide identity 77%). The complete viral genome sequence of additional HPV199 isolate was determined from anal canal swab sample. Two HPV199 complete viral sequences exhibit 99.4% nucleotide identity. To the best of our knowledge, this is the first member of Gamma-PV with complete nucleotide sequences determined from two independent clinical samples. To evaluate the tissue tropism of the novel HPV type, 916 clinical samples were tested using HPV199 type-specific real-time PCR: HPV199 was detected in 2/76 tissue samples of histologically confirmed common warts, 2/108 samples of eyebrow hair follicles, 2/137 anal canal swabs obtained from individuals with clinically evident anal pathology, 4/184 nasopharyngeal swabs and 3/411 cervical swabs obtained from women with normal cervical cytology. Although HPV199 was found in 1.4% of cutaneous and mucosal samples only, it exhibits dual tissue tropism. According to the results of our study and literature data, dual tropism of all Gamma-12 members is highly possible.

A highly divergent human papillomavirus, named HPV-CH2, was identified in fecal samples from children with diarrhea in China by 454 high-throughput sequencing. Here, we report the complete genome sequence and genetic organization of the virus. The full-length nucleotide sequence of HPV-CH2 shares the highest sequence similarity with HPV-156, with 72 % nucleotide sequence identity. The L1 gene of the HPV-CH2 shared <70 % nucleotide identity with previously reported HPVs, suggesting HPV-CH2 as a new type of papillomavirus. Phylogenetic analysis revealed that the HPV-CH2 belongs to the genus Gammapapillomavirus . No HPV-CH2 was detected by PCR in samples from children with both gastroenteritis and respiratory infection.

Genus-β human papillomavirus (HPV) DNA has been detected in basal cell carcinoma (BCC) tumors, but most epidemiologic studies have not observed associations between genus-β HPV seropositivity and BCC. A clinic-based case–control study was conducted to investigate cutaneous HPV infection in BCC. BCC cases (n=224) were recruited from a dermatology clinic, and controls (n=300) were patients who were screened negative for skin cancer. Antibodies against cutaneous HPV types in genera α, β, γ, mu, and nu were measured, and tumors from a subset of BCC cases (n=195) were tested for HPV DNA. Overall associations were observed between BCC and seropositivity for HPV types in genus-α (odds ratio (OR)=1.61; 95% confidence interval (CI)=1.11–2.35), γ (OR=1.78; 95% CI=1.22–2.60), and mu (OR=1.56; 95% CI=1.06–2.30). BCC cases with β-HPV DNA in their tumors were more likely to be β-HPV seropositive than controls (OR=1.76; 95% CI=1.03–3.01), with type-specific associations observed for HPV8 and HPV23, whereas no association was observed between β-HPV seropositivity and β-HPV DNA–negative BCC. No concordance between seropositivity and tumor DNA status was observed for HPV types in genera α and γ. In conclusion, the combined serology and tumor DNA results suggest that β HPV types may have a role in BCC. Additional studies of BCC that assess HPV types in multiple genera are needed.

The novel human papillomavirus type 154 (HPV154) was characterized from a wart on the crena ani of a three-year-old boy. It was previously designated as the putative HPV type FADI3 by sequencing of a subgenomic FAP amplicon. We obtained the complete genome by combined methods including rolling circle amplification (RCA), genome walking through an adapted method for detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR), long-range PCR, and finally by cloning of four overlapping amplicons. Phylogenetically, the HPV154 genome clustered together with members of the proposed species Gammapapillomavirus 11, and demonstrated the highest identity in L1 to HPV136 (68.6%). The HPV154 was detected in 3% (2/62) of forehead skin swabs from healthy children. In addition, the different detection sites of 62 gammapapillomaviruses were summarized in order to analyze their tissue tropism. Several of these HPV types have been detected from multiple sources such as skin, oral, nasal, and genital sites, suggesting that the gammapapillomaviruses are generalists with a broader tissue tropism than previously appreciated. The study expands current knowledge concerning genetic diversity and tropism among HPV types in the rapidly growing gammapapillomavirus genus.

Background Human papillomaviruses (HPVs) have been divided into mucosal and cutaneous types according to their primary epithelial tissue tropism. However, recent studies showed the presence of several cutaneous types in mucosal lesions and healthy mucosa from different anatomical sites. Methods Here, the HPV prevalence and type-specific distribution were assessed in a variety of mucosal samples from 435 individuals using a combination of two established broad-spectrum primer systems: Gamma -PV PCR and CUT PCR. Results Overall HPV prevalence in anal canal swabs, cervical cancer biopsies, genital warts and oral swabs was 85, 47, 62 and 4%, respectively. In anal canal swabs, Alpha -PVs were most frequently found (59%), followed by Gamma - (37%) and Beta -PVs (4%). The prevalence and persistence of HPV infection in the anal canal of 226 individuals were further explored. Overall HPV, Gamma -PVs and multiple HPV infections were significantly higher in men vs. women ( p  = 0.034, p  = 0.027 and p  = 0.003, respectively); multiple HPV infections were more common in individuals ≤40 years ( p  = 0.05), and significantly higher prevalence of Gamma -PVs and multiple HPV infections was observed in HIV-1-positive vs. HIV-1-negative individuals ( p  = 0.003 and p  = 0.04, respectively). Out of 21 patients with follow-up anal swabs, only one persistent infection with the same type (HPV58) was detected. Conclusions Our findings suggest that Gamma -PVs (except species Gamma -6) are ubiquitous viruses with dual muco-cutaneous tissue tropism. Anal canal Gamma -PV infections may be associated with sexual behavior and the host immune status. This study expands the knowledge on Gamma -PVs’ tissue tropism, providing valuable data on the characteristics of HPV infection in the anal canal.

Gammapapillomavirus (Gamma-PV) is a diverse and rapidly expanding PV-genus, currently consisting of 76 fully characterized human papillomavirus (HPV) types. In this study, DNA genomes of two novel HPV types, HPV179 and HPV184, obtained from two distinct facial verrucae vulgares specimens of a 64 year-old renal-transplant recipient, were fully cloned, sequenced and characterized. HPV179 and HPV184 genomes comprise 7,228-bp and 7,324-bp, respectively, and contain four early (E1, E2, E6 and E7) and two late genes (L1 and L2); the non-coding region is typically positioned between L1 and E6 genes. Phylogenetic analysis of the L1 nucleotide sequence placed both novel types within the Gamma-PV genus: HPV179 was classified as a novel member of species Gamma-15, additionally containing HPV135 and HPV146, while HPV184 was classified as a single member of a novel species Gamma-25. HPV179 and HPV184 type-specific quantitative real-time PCRs were further developed and used in combination with human beta-globin gene quantitative real-time PCR to determine the prevalence and viral load of the novel types in the patient's facial warts and several follow-up skin specimens, and in a representative collection, a total of 569 samples, of HPV-associated benign and malignant neoplasms, hair follicles and anal and oral mucosa specimens obtained from immunocompetent individuals. HPV179 and HPV184 viral loads in patients' facial warts were estimated to be 2,463 and 3,200 genome copies per single cell, respectively, suggesting their active role in the development of common warts in organ-transplant recipients. In addition, in this particular patient, both novel types had established a persistent infection of the skin for more than four years. Among immunocompetent individuals, HPV179 was further detected in low-copy numbers in a few skin specimens, indicating its cutaneous tissue tropism, while HPV184 was further detected in low-copy numbers in one mucosal and a few skin specimens, suggesting its dual tissue tropism.

•A novel 4-valent vaccine induces good immune response to HPV types 6/11/16/18.•A newly developed 9-valent HPV vaccine was highly immunogenic.•Both of the investigated vaccines were generally well tolerated among females 20–45 years old.•The new vaccines show non-inferiority in immunogenicity and safety comparing with Gardasil-4. Human papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent). 1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20–26, 27–35, or 36–45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference > −10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio > 0.5. Among the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded −10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios > 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths. This study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.