Abstract
A subset of human papillomavirus (HPV) infections is causally related to the development of human epithelial tumors and cancers. Like a number of pathogens, HPV entry into target cells is initiated by first binding to heparan sulfonated proteoglycan (HSPG) cell surface attachment factors. The virus must then move to distinct secondary receptors, which are responsible for particle internalization. Despite intensive investigation, the mechanism of HPV movement to and the nature of the secondary receptors have been unclear. We report that HPV16 particles are not liberated from bound HSPG attachment factors by dissociation, but rather are released by a process previously unreported for pathogen-host cell interactions. Virus particles reside in infectious soluble high molecular weight complexes with HSPG, including syndecan-1 and bioactive compounds, like growth factors. Matrix mellatoproteinase inhibitors that block HSPG and virus release from cells interfere with virus infection. Employing a co-culture assay, we demonstrate HPV associated with soluble HSPG-growth factor complexes can infect cells lacking HSPG. Interaction of HPV-HSPG-growth factor complexes with growth factor receptors leads to rapid activation of signaling pathways important for infection, whereas a variety of growth factor receptor inhibitors impede virus-induced signaling and infection. Depletion of syndecan-1 or epidermal growth factor and removal of serum factors reduce infection, while replenishment of growth factors restores infection. Our findings support an infection model whereby HPV usurps normal host mechanisms for presenting growth factors to cells via soluble HSPG complexes as a novel method for interacting with entry receptors independent of direct virus-cell receptor interactions.
Highlights
Human papillomaviruses (HPVs) are small, DNA-containing viruses that infect mucosal and cutaneous epithelium to cause benign and malignant tumors, including many anogenital, oropharyngeal and some skin cancers [1,2]
Relatively little is known about the mechanism(s) that triggers the translocation of HPV from heparan sulfonated proteoglycan (HSPG) to the receptors that facilitate entry
Bound HPV particles are liberated from cells in an active complex with HSPGs and growth factors rather than dissociating from the sugars to engage secondary receptors
Summary
Human papillomaviruses (HPVs) are small, DNA-containing viruses that infect mucosal and cutaneous epithelium to cause benign and malignant tumors, including many anogenital, oropharyngeal and some skin cancers [1,2]. Like a number of other pathogens, HPV entry into target cells is a multistep process initiated by binding to cell surface attachment factors, the most common of which are glycosaminoglycan chains, especially heparan sulfate in proteoglycans (HSPGs) [3,4]. Binding to these negatively charged polysaccharides is usually electrostatic and relatively nonspecific. Many microbes like HPVs must transfer from HSPG to a distinct secondary receptor responsible for active pathogen internalization [5]. For HPVs this entry receptor has been elusive. The mechanism of HPV movement from primary HSPG attachment receptors to secondary high-affinity receptors has been unclear
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