Abstract
A significant proportion of recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6). The long control region (LCR) contains cis-elements for regulation of transcription. Our aim was to characterize LCR HPV-6 variants in RRP cases, compare promoter activity of these isolates and search for cellular transcription factors (TFs) that could explain the differences observed. The complete LCR from 13 RRP was analyzed. Transcriptional activity of 5 variants was compared using luciferase assays. Differences in putative TFs binding sites among variants were revealed using the TRANSFAC database. Chromatin immunoprecipation (CHIP) and luciferase assays were used to evaluate TF binding and impact upon transcription, respectively. Juvenile-onset RRP cases harbored exclusively HPV-6vc related variants, whereas among adult-onset cases HPV-6a variants were more prevalent. The HPV-6vc reference was more transcriptionally active than the HPV-6a reference. Active FOXA1, ELF1 and GATA1 binding sites overlap variable nucleotide positions among isolates and influenced LCR activity. Furthermore, our results support a crucial role for ELF1 on transcriptional downregulation. We identified TFs implicated in the regulation of HPV-6 early gene expression. Many of these factors are mutated in cancer or are putative cancer biomarkers, and must be further studied.
Highlights
Recurrent Respiratory Papillomatosis (RRP) is characterized by the proliferation of multiple papillomas within the respiratory tract affecting especially the larynx [1,2]
Based on age distribution of affected individuals, RRP has been clinically divided into juvenile onset (JORRP) and adult onset RRP (AORRP) [3]
We sequenced the long control region (LCR) of 23 human papillomavirus type 6 (HPV-6) RRP specimens obtained from 13 patients
Summary
Recurrent Respiratory Papillomatosis (RRP) is characterized by the proliferation of multiple papillomas within the respiratory tract affecting especially the larynx [1,2]. RRP can affect persons of all ages; but a bimodal age distribution is often observed: disease peaks in children younger than 5 years and between the third and fourth decade of life. RRP is considered a benign disease, high recurrence rates are associated to significant morbidity and is occasionally fatal [5]. Because the term subtype was redefined, HPV-6a, -6b, and -6vc were assigned to molecular variants since nucleotide sequence among these isolates diverges less than 2% within the L1 gene [8]. The analysis of 190 complete viral genomes clustered HPV-6 isolates into two variants lineages named A and B with the latter enclosing 5 sublineages (differences in whole genome sequence of 0.5–1.0%) [9]. While the HPV-6b-reference isolate is one of the highly related members of lineage A, HPV-6vc and HPV-6a sort to B1 and B3 sublineages, respectively [10]
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