Global Genomic Diversity of Human Papillomavirus 6 Based on 724 Isolates and 190 Complete Genome Sequences

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. Fil: Jelen, Mateja M. University of Ljubljana; Eslovenia Fil: Chen, Zigui. Albert Einstein College of Medicine. New York; Estados Unidos Fil: Kocjan, Botjan J.. University of Ljubljana; Eslovenia Fil: Burt, Felicity J.. University of the Free State. Bloemfontein; Sudáfrica Fil: Chan, Paul K.S.. Chinese University of Hong Kong; China Fil: Chouhy, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Combrinck, Catharina E.. University of the Free State. Bloemfontein; Sudáfrica Fil: Coutlee, Francois. Hôpital Notre-Dame-Pavillon Deschamps. Montréal; Canadá Fil: Estrade, Christine. Lausanne University Hospital; Suiza Fil: Ferenczy, Alex. McGill University and Jewish General Hospital. Montreal; Canadá Fil: Fiander, Alison. Institute of Cancer and Genetics. Cardiff; Reino Unido Fil: Franco, Eduardo L.. McGill University. Montreal; Canadá Fil: Garland, Suzanne M.. The Royal Women's Hospital. Parkville; Australia. The University of Melbourne; Australia. Murdoch Children's Research Institute. Victoria; Australia Fil: Giri, Adriana Angelica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: González, Joaquín Víctor. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina Fil: Gröning, Arndt. Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH. Hannover; Alemania Fil: Heidrich, Kerstin. Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH. Hannover; Alemania Fil: Hibbitts, Sam. Institute of Cancer and Genetics. Cardiff; Reino Unido Fil: Hosnjak, Lea. University of Ljubljana; Eslovenia Fil: Luk, Tommy N.M. The Chinese University of Hong Kong; China. Hong Kong Special Administrative Region; China Fil: Marinic, Karina. Hospital Dr. Julio C. Perrando. Chaco; Argentina Fil: Matsukura, Toshihiko. National Institute of Health. Tokyo; Japón Fil: Neumann, Anna. The University of Melbourne; Australia. Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH. Hannover; Alemania Fil: Oštrbenk, Anja. University of Ljubljana; Eslovenia Fil: Picconi, Maria Alejandra. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud; Argentina Fil: Richardson, Harriet. Queen's University. Ontario; Canadá Fil: Sagadin, Martin. University of Ljubljana; Eslovenia Fil: Sahli, Roland. Lausanne University Hospital; Suiza Fil: Seedat, Riaz Y.. University of the Free State. Bloemfontein; Sudáfrica Fil: Seme, Katja. University of Ljubljana; Eslovenia Fil: Severini, Alberto. Public Health Agency of Canada. Winnipeg; Canadá Fil: Sinchi, Jessica L. Hospital Dr. Julio C. Perrando. Chaco; Argentina Fil: Smahelova, Jana. Institute of Hematology and Blood Transfusion. Praga; República Checa Fil: Tabrizi, Sepehr N.. The University of Melbourne; Australia. Murdoch Children's Research Institute. Victoria; Australia. The Royal Women's Hospital. Parkville; Australia Fil: Tachezy, Ruth. Institute of Hematology and Blood Transfusion. Praga; República Checa Fil: Tohme, Sarah. Public Health Agency of Canada. Winnipeg; Canadá Fil: Uloza, Virgilijus. Lithuanian University of Health Sciences. Kaunas; Lituania Fil: Vitkauskiene, Astra. Lithuanian University of Health Sciences. Kaunas; Lituania Fil: Wong, Yong Wee. Universti Kebangsaan Malaysia. Bangi; Malasia Fil: Lepeja, Snježana Židovec. University Hospital for Infectious Diseases Dr. Fran Mihaljević. Zagreb; Croacia Fil: Burk, Robert D.. Albert Einstein College of Medicine.New York; Estados Unidos Fil: Poljak, Mario. Albert Einstein College of Medicine. New York; Estados Unidos