title: Global genomic diversity of human papillomavirus 6 based on 724 isolates and 190 complete genome sequences.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Mateja M
authors.initials: MM
authors.lastname: Jelen
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Zigui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Boštjan J
authors.initials: BJ
authors.lastname: Kocjan
authors.affiliation: Department of Medical Microbiology and Virology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
authors.forename: Felicity J
authors.initials: FJ
authors.lastname: Burt
authors.affiliation: Department of Microbiology, Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Paul K S
authors.initials: PK
authors.lastname: Chan
authors.affiliation: Human Virology Group, National Council of Scientific and Technical Research, Institute of Molecular and Cell Biology of Rosario, Rosario, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Chouhy
authors.affiliation: Department of Medical Microbiology and Virology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
authors.forename: Catharina E
authors.initials: CE
authors.lastname: Combrinck
authors.affiliation: Laboratoire de Virologie Moléculaire, Centre de Recherche, Centre Hospitalier de L'Université de Montréal, Hôpital Notre-Dame-Pavillon Deschamps, Montréal, Québec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Coutlée
authors.affiliation: Lausanne University Hospital (CHUV), Institute of Microbiology, Lausanne, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Estrade
authors.affiliation: Department of Pathology, McGill University and Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Ferenczy
authors.affiliation: Department of Obstetrics and Gynaecology, Cardiff University School of Medicine, Institute of Cancer and Genetics, Cardiff, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Fiander
authors.affiliation: Department of Oncology, Division of Cancer Epidemiology, McGill University, Montréal, Québec, Canada.
authors.forename: Eduardo L
authors.initials: EL
authors.lastname: Franco
authors.affiliation: Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Parkville, Victoria, Australia Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Garland
authors.affiliation: Human Virology Group, National Council of Scientific and Technical Research, Institute of Molecular and Cell Biology of Rosario, Rosario, Argentina.
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Giri
authors.affiliation: Oncogenic Viruses Service, National Institute of Infectious Diseases-ANLIS Dr. Carlos G. Malbrán, Buenos Aires, Argentina.
authors.forename: Joaquín Víctor
authors.initials: JV
authors.lastname: González
authors.affiliation: Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH, Hannover, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Gröning
authors.affiliation: Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH, Hannover, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heidrich
authors.affiliation: Department of Obstetrics and Gynaecology, Cardiff University School of Medicine, Institute of Cancer and Genetics, Cardiff, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Hibbitts
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Lea
authors.initials: L
authors.lastname: Hošnjak
authors.affiliation: Dermatology Research Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China Department of Health, Social Hygiene Service, Centre for Health Protection, Hong Kong Special Administrative Region, China.
authors.forename: Tommy N M
authors.initials: TN
authors.lastname: Luk
authors.affiliation: Histocompatibility and Molecular Genetics Laboratory, Dr. Julio C. Perrando Hospital, Resistencia, Chaco, Argentina.
authors.forename: Karina
authors.initials: K
authors.lastname: Marinic
authors.affiliation: Ganshintetsu Memorial Laboratory, Department of Virology II, National Institute of Health, Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Matsukura
authors.affiliation: Medizinisches Versorgungszentrum wagnerstibbe für Laboratoriumsmedizin und Pathologie GmbH, Hannover, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Neumann
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Oštrbenk
authors.affiliation: Oncogenic Viruses Service, National Institute of Infectious Diseases-ANLIS Dr. Carlos G. Malbrán, Buenos Aires, Argentina.
authors.forename: Maria Alejandra
authors.initials: MA
authors.lastname: Picconi
authors.affiliation: Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: Harriet
authors.initials: H
authors.lastname: Richardson
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Martin
authors.initials: M
authors.lastname: Sagadin
authors.affiliation: Lausanne University Hospital (CHUV), Institute of Microbiology, Lausanne, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Sahli
authors.affiliation: Department of Otorhinolaryngology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
authors.forename: Riaz Y
authors.initials: RY
authors.lastname: Seedat
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Katja
authors.initials: K
authors.lastname: Seme
authors.affiliation: Viral Exanthemata and STD Section, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Alberto
authors.initials: A
authors.lastname: Severini
authors.affiliation: Histocompatibility and Molecular Genetics Laboratory, Dr. Julio C. Perrando Hospital, Resistencia, Chaco, Argentina.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Sinchi
authors.affiliation: Department of Experimental Virology, National Reference Laboratory for Papillomaviruses, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Smahelova
authors.affiliation: Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Parkville, Victoria, Australia Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors.forename: Sepehr N
authors.initials: SN
authors.lastname: Tabrizi
authors.affiliation: Department of Experimental Virology, National Reference Laboratory for Papillomaviruses, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tachezy
authors.affiliation: Viral Exanthemata and STD Section, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tohme
authors.affiliation: Department of Otolaryngology, Lithuanian University of Health Sciences, Medical Academy, Kaunas, Lithuania.
authors.forename: Virgilijus
authors.initials: V
authors.lastname: Uloza
authors.affiliation: Department of Laboratory Medicine, Lithuanian University of Health Sciences, Medical Academy, Kaunas, Lithuania.
authors.forename: Astra
authors.initials: A
authors.lastname: Vitkauskiene
authors.affiliation: DNA Laboratories Sdn. Bhd., UKM-MTDC Technology Centre, Universti Kebangsaan Malaysia, Bangi, Malaysia.
authors.forename: Yong Wee
authors.initials: YW
authors.lastname: Wong
authors.affiliation: Department of Molecular Diagnostics, University Hospital for Infectious Diseases Dr. Fran Mihaljević, Zagreb, Croatia.
authors.forename: Snježana
authors.initials: S
authors.lastname: Zidovec Lepej
authors.affiliation: Departments of Microbiology and Immunology, Epidemiology and Population Health, Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, New York, New York, USA Department of Pediatrics, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.affiliation: Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia mario.poljak@mf.uni-lj.si.
authors.forename: Mario
authors.initials: M
authors.lastname: Poljak
mesh_terms: D001005:Anus Neoplasms / Q000150:complications / Q000235:genetics* / Q000821:virology; D005075:Biological Evolution; D019070:Cell Lineage; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D016679:Genome, Viral / Q000235:genetics*; D023281:Genomics / Q000379:methods; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000150:complications / Q000235:genetics* / Q000821:virology; D052163:Human papillomavirus 6 / Q000235:genetics* / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics* / Q000821:virology; D010802:Phylogeny; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000235:genetics* / Q000821:virology
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