Genomic differences in the background of different severity in juvenile-onset respiratory papillomatoses associated with
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ORIGINAL INVESTIGATION
Genomic differences in the background of different severity in juvenile-onset respiratory papillomatoses associated with human papillomavirus type 11 Tama´s Ga´ll • Andrea Kis • Tı´mea Zso´fia Tata´r • Ga´bor Kardos • Lajos Gergely • Krisztina Szarka
Received: 19 December 2012 / Accepted: 22 April 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract This study aimed to compare complete genome sequences of human papillomavirus (HPV) type 11 from two solitary papillomas (considered minimally aggressive), two moderately (six and nine episodes) and two highly aggressive (30 and 33 episodes) juvenile-onset respiratory papillomatoses. Genomic regions were sequenced using the Sanger method; sequences were compared to available GenBank genomes. Activity of the long control region (LCR) was assessed in HEp-2 cell line using luciferase assays and compared to that of the reference (GenBank Accession Number M14119). Site-directed mutagenesis was performed to confirm the association of polymorphisms with differences in LCR activity. Eleven alterations resulted in amino acid changes in different open reading frames. A72E in E1 and Q86K in E2 proteins were exclusively present in a moderately aggressive disease, L1 alterations A476V and S486F were unique to a severe papillomatosis. HPV11s in both solitary papillomas had identical LCRs containing a T7546C polymorphism, which strongly attenuated LCR activity, as confirmed by sitedirected mutagenesis. This strong attenuator polymorphism was also present in the other four genomes showing significantly higher activities, but in these other alterations with demonstrable but statistically not significant attenuating (A7413C, 7509 T deletion) or enhancing (C7479T, T7904A) effect on transactivating potential (as demonstrated by site-directed mutagenesis) were also detected. LCR activities corresponded well to severity, excepting the
T. Ga´ll A. Kis T. Z. Tata´r G. Kardos L. Gergely K. Szarka (&) Department of Medical Microbiology, Medical and Health Science Centre, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary e-mail: [email protected]
highly aggressive papillomatosis with the L1 alterations. Presence of intratypic variants cannot explain differences in severity of respiratory papillomatoses associated with HPV11; virulence seems to be determined by the interaction of multiple genetic differences. Keywords HPV11 Complete genome comparison LCR activity Clinical course
Introduction Respiratory papillomas are mainly caused by low-risk human papillomaviruses (HPVs) HPV6 and HPV11 [1–3]. Papillomatosis associated with HPV11 is considered more aggressive than the disease related to HPV6, that is, it is more frequently complicated by spreading to extralaryngeal sites or by malignant transformation, but the severity of different cases associated with HPV11 is also variable [4–7]. The cause for this difference in clinical course remains elusive; both host- and virus-derived factors may play a role. Host immune response patterns
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