Human Papillomaviruses (HPVs) are circular double-stranded DNA (dsDNA) viruses that infect human cutaneous and mucosal tissue. Most HPV infections are benign or cause only minor pathologies. However, infection with one of the ~15 high risk types of HPV is associated with a variety of head/neck and anogenital cancers. All told, HPV infection is thought to cause ~5% of all human cancers and cause ~275,000 deaths per year. Despite causing immense morbidity and mortality, many aspects of how HPV virions successfully establish infection in host cells remain poorly characterized. Infection begins with HPV virions binding the cell surface, where they are modified by the host protease furin. The HPV virions are then endocytosed by association with an unknown entry receptor(s). After endocytosis the HPV minor capsid protein L2 acts as a chaperone to ensure that the viral genome (vDNA) traffics from endosomes to the trans-Golgi network (TGN) and eventually the nucleus, where HPV replication occurs. En route to the nucleus, the L2/vDNA complex must translocate across limiting intracellular membranes. The details of these critical processes remain poorly characterized. In this work we investigate the viral and host factors involved in the penetration of host membranes by the HPV L2/vDNA complex. First, we elucidated many of the viral and host factors necessary for furin cleavage of L2. We also demonstrate that furin cleavage mediates the homo-oligomerization and membrane insertion of L2. Finally we demonstrate that complete translocation across the limiting membrane is dependent on host cell entry into mitosis. Overall this work provides novel insight into the molecular mechanisms used by HPV virions to breach host membranes and establish infection.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/623159 |
| Date | January 2016 |
| Creators | Bronnimann, Matthew Phillip, Bronnimann, Matthew Phillip |
| Contributors | Goodrum Sterling, Felicia D., Goodrum Sterling, Felicia D., Campos, Samuel K., Frelinger, Jeffrey A., Lybarger, Lonnie P., Wilson, Jean M. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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