Biomedical Sciences ETDs

Publication Date

5-1-2012

Abstract

Human papillomaviruses (HPVs) are the causative agent of cervical cancer and infect skin and mucosal membranes. Through wounding the virus establishes infection in the basal layer of human keratinocytes and requires differentiating squamous epithelium to complete the viral life cycle. HPV virions contain two structural viral proteins: the major capsid protein L1 that self-assembles into capsid structures, and the minor capsid protein, L2, that is essential for infection. It is believed that HPV cellular entry occurs via receptor-mediated endocytosis and that the primary attachment factors used by the virus are heparan sulfonated proteoglycans (HSPGs). Most current HPV literature follows an entry model whereby L1 binds to HSPGs, causing a conformational change in the capsid, thus allowing access to a furin/proprotein convertase (PC) cleavage site on L2. Once L2 is furin-cleaved, the virus binds to a yet unknown secondary internalization receptor(s). There is, however, a body of experimental evidence that does not support this entry model. For example, L1-only virus like particles (VLPs) are able to enter cells with similar kinetics as L1/L2 VLPs and mutagenesis of the L2 furin cleavage site does not abrogate the virions ability to enter the cell. Furthermore, recent research in our laboratory indicates an alternative mechanism of HPV infection, whereby the virus binds to cell-anchored HSPGs that are normally in complex with a variety of ligands including growth factors (GF), cytokines, extracellular matrix (ECM) proteins, and proteinases. Ectodomain shedding of syndecan-1 and HSPG by matrix metalloproteinases (MMPs) allows the HPV-HSPG-GF complexes to become soluble and move to secondary GF receptors, thereby allowing the virus to gain access to the cell. While MMPs are known to activate many biological molecules, they themselves are activated by furin/PCs. Due to these new observations and the existence of experimental evidence that does not support the current model of HPV infection, we postulate that the function of furin has been misinterpreted. Our data suggest that a cellular component important for the infection process is also a target of furin/PC activity. Furthermore, we have found that multiple PC members play roles at different steps of HPV infection.

Keywords

HPV, Furin

Document Type

Thesis

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Masters

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Lidke, Diane

Second Committee Member

Kajon, Adriana

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