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.

Fig 1

HPV16 binds to heparin sulfate proteoglycans (HSPGs) on either the epithelial cell surface or the basement membrane or through laminin-332 on the ECM. Epidermal growth factor receptor (EGFR) and/or keratinocyte growth factor receptor (KGFR) may also become activated at this time through HSPG/growth factor HPV16 complexes and may initiate intracellular signaling cascades that include the activation of the phosphoinositide 3-kinase (PI3K) pathway. After binding to HSPGs, the virion undergoes a conformational change that is facilitated by cyclophilin B (CyPB), which exposes more amino acids of the N terminus of L2. Subsequently, HPV16 binds to α6 integrin, which initiates a second intracellular signaling cascade. After undergoing conformational changes and signaling, the HPV16 capsid binds to A2t. Upon HPV binding to the A2t, clathrin-, caveolin-, lipid raft-, flotillin-, cholesterol-, and dynamin-independent endocytosis of HPV16 is triggered. HPV16-induced PI3K activation may then be involved in vesicle closure and actin scission. Tetraspanins are hypothesized to be involved in forming an enriched membrane domain that stabilizes connections between HPV16-associated molecules. Therefore, as opposed to a sequential handoff of the virion from one receptor to another, we hypothesize that a receptor complex coalesces and includes HSPGs, CyPB, α6 integrin, tetraspanins, EGFR, and A2t.