title: The evolving field of human papillomavirus receptor research: a review of binding and entry.
abstract: Human papillomaviruses (HPVs) infect epithelia and can lead to the development of lesions, some of which have malignant potential. HPV type 16 (HPV16) is the most oncogenic genotype and causes various types of cancer, including cervical, anal, and head and neck cancers. However, despite significant research, our understanding of the mechanism by which HPV16 binds to and enters host cells remains fragmented. Over several decades, many HPV receptors and entry pathways have been described. This review puts those studies into context and offers a model of HPV16 binding and entry as a framework for future research. Our model suggests that HPV16 binds to heparin sulfate proteoglycans (HSPGs) on either the epithelial cell surface or basement membrane through interactions with the L1 major capsid protein. Growth factor receptors may also become activated through HSPG/growth factor/HPV16 complexes that initiate signaling cascades during early virion-host cell interactions. After binding to HSPGs, the virion undergoes conformational changes, leading to isomerization by cyclophilin B and proprotein convertase-mediated L2 minor capsid protein cleavage that increases L2 N terminus exposure. Along with binding to HSPGs, HPV16 binds to α6 integrins, which initiate further intracellular signaling events. Following these primary binding events, HPV16 binds to a newly identified L2-specific receptor, the annexin A2 heterotetramer. Subsequently, clathrin-, caveolin-, lipid raft-, flotillin-, cholesterol-, and dynamin-independent endocytosis of HPV16 occurs.
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, Los Angeles, California, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Raff
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Woodham
authors.forename: Laura M
authors.initials: LM
authors.lastname: Raff
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Skeate
authors.forename: Lisa
authors.initials: L
authors.lastname: Yan
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.forename: Mario
authors.initials: M
authors.lastname: Schelhaas
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D052685:Alphapapillomavirus / Q000235:genetics / Q000502:physiology*; D000818:Animals; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000821:virology; D011991:Receptors, Virus / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D019812:Heparan Sulfate Proteoglycans; D011991:Receptors, Virus
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