Global Genomic Diversity of Human Papillomavirus 6 Based on 724 Isolates and 190 Complete Genome Sequences
Authors: Jelen Mateja M. , Chen Zigui , Kocjan Boštjan J. , Burt Felicity J. , Chan Paul K. S. , Chouhy Diego , Combrinck Catharina E. , Coutlée François , Estrade Christine , Ferenczy Alex , Fiander Alison , Franco Eduardo L. , Garland Suzanne M. , Giri Adriana A. , González Joaquín Víctor , Gröning Arndt , Heidrich Kerstin , Hibbitts Sam , Hošnjak Lea , Luk Tommy N. M. , Marinic Karina , Matsukura Toshihiko , Neumann Anna , Oštrbenk Anja , Picconi Maria Alejandra , Richardson Harriet , Sagadin Martin , Sahli Roland , Seedat Riaz Y. , Seme Katja , Severini Alberto , Sinchi Jessica L. , Smahelova Jana , Tabrizi Sepehr N. , Tachezy Ruth , Tohme Sarah , Uloza Virgilijus , Vitkauskiene Astra , Wong Yong Wee , Židovec Lepej Snježana , Burk Robert D. , Poljak Mario 
Published: April 2014

Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution.

IMPORTANCE
This study established the largest database of globally circulating HPV6 genomic variants and contributed a total of 130 new, complete HPV6 genome sequences to available sequence repositories. Two HPV6 variant lineages and five sublineages were identified and showed some degree of association with geographical location, anatomical site of infection/disease, and/or gender. We additionally identified several HPV6 lineage- and sublineage-specific SNPs to facilitate the identification of HPV6 variants and determined a representative region within the L2 gene that is suitable for HPV6 whole-genome-based phylogenetic analysis. This study complements and significantly expands the current knowledge of HPV6 genetic diversity and forms a comprehensive basis for future epidemiological, evolutionary, functional, pathogenicity, vaccination, and molecular assay development studies.