Global Genomic Diversity of Human Papillomavirus 11 Based on 433 Isolates and 78 Complete Genome Sequences

Abstract

Human papillomavirus 11 (HPV11) is an etiological agent of anogenital warts and laryngeal papillomas and is included in the 4-valent and 9-valent prophylactic HPV vaccines. We established the largest collection of globally circulating HPV11 isolates to date and examined the genomic diversity of 433 isolates and 78 complete genomes (CGs) from six continents. The genomic variation within the 2,800-bp E5a-E5b-L1-upstream regulatory region was initially studied in 181/207 (87.4%) HPV11 isolates collected for this study. Of these, the CGs of 30 HPV11 variants containing unique single nucleotide polymorphisms (SNPs), indels (insertions or deletions), or amino acid changes were fully sequenced. A maximum likelihood tree based on the global alignment of 78 HPV11 CGs (30 CGs from our study and 48 CGs from GenBank) revealed two HPV11 lineages (lineages A and B) and four sublineages (sublineages A1, A2, A3, and A4). HPV11 (sub)lineage-specific SNPs within the CG were identified, as well as the 208-bp representative region for CG-based phylogenetic clustering within the partial E2 open reading frame and noncoding region 2. Globally, sublineage A2 was the most prevalent, followed by sublineages A1, A3, and A4 and lineage B. IMPORTANCEThis collaborative international study defined the global heterogeneity of HPV11 and established the largest collection of globally circulating HPV11 genomic variants to date. Thirty novel complete HPV11 genomes were determined and submitted to the available sequence repositories. Global phylogenetic analysis revealed two HPV11 variant lineages and four sublineages. The HPV11 (sub)lineage-specific SNPs and the representative region identified within the partial genomic region E2/noncoding region 2 (NCR2) will enable the simpler identification and comparison of HPV11 variants worldwide. This study provides an important knowledge base for HPV11 for future studies in HPV epidemiology, evolution, pathogenicity, prevention, and molecular assay development. Human papillomavirus 11 (HPV11), which belongs to species 10 of the Alphapapillomavirus genus (Alpha-PV), is etiologically associated with approximately 20% of anogenital warts and 30 to 40% of laryngeal papillomas (1-11). HPV11 is generally considered a low-risk HPV type due to its rare presence in HPVrelated cancers in humans, especially cervical cancer (9). HPV11 is present in 0.5% of samples from HPV-positive women with a normal cytology worldwide and causes 2.3% of cervical low-grade squamous cell intraepithelial lesions (12, 13). However, rare case reports of HPV11-positive cases of cervical and anal squamous cell carcinomas, malignantly transformed laryngeal papillomas, and sinonasal inverted papillomas associated with squamous cell carcinoma can be found in the literature (14-21). Due to its clinical significance, HPV11 has been included in the current quadrivalent and nonavalent prophylactic HPV vaccines (22,23).The genetic diversity of HPV11 was studied for the first time in 1995, when Heinzel et al. sequenced the noncoding upstre...

HPV-6 molecular variants association with the development of genital warts in men: The HIM Study

“…Several studies have suggested that high-risk HPV-16 and HPV-18 coevolved with the human species and that the distribution of variants of both viral types varies geographically [20][21][22]. However, with regard to variants of low-risk HPV types, only slight geographical correlations have been reported, which strongly suggest that HPV-6 and HPV-11 variants are detected with similar frequencies around the world [10,15,16,23]. In the present study, HPV-6 B3 variants predominated in all 3 countries among genital swabs of controls, although these variants were significantly less frequent in men from Brazil and the United States compared to men from Mexico.…”

<p>Juvenile-Onset Recurrent Respiratory Papillomatosis Diagnosis and Management – A Developing Country Review</p>

“…64 Intratypic variants of HPV6 and HPV11 have been also been shown to vary by geographic area, but not to be as geographically restricted. 65,66 The possible role of intratypic variants in differences in severity of respiratory papillomatosis is unclear but may be a result of combinations of alterations in the viral genome. 64 The E5, E6 and E7 open reading frames have generally been found to be conserved across variants, suggesting that they play little role in differences in clinical behavior.…”

Lack of Association between Human Papillomavirus Types 6 and 11 Genetic Variants and Cervical Abnormalities: The Ludwig–McGill Cohort Study

“…A fraction of cervical low-grade squamous intraepithelial lesions (LSIL) are caused by low-risk HPVs 6 and 11 (1). Whole-genome variations of 1%-10% and 0.5%-1% define HPV variant lineages and sublineages, respectively (2,3). Phylogenetic analysis of isolates collected worldwide clusters variants of HPVs 6 and 11 into two lineages termed A and B, additionally divided into sublineages (2,3).…”

“…Whole-genome variations of 1%-10% and 0.5%-1% define HPV variant lineages and sublineages, respectively (2,3). Phylogenetic analysis of isolates collected worldwide clusters variants of HPVs 6 and 11 into two lineages termed A and B, additionally divided into sublineages (2,3). We recently showed that although HPV6 B1 variants are associated with an increased risk for male genital warts (GW) compared with non-B1 variants (4), GW risk was not affected by HPV11 intratypic variability (5).…”