Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus

•HPV16 virions preferentially bind to components of the extracellular matrix.•Internalization requires conformational changes in both capsid proteins.•Uncoating triggers membrane penetration by L2 protein to interact with cytosolic factors for transport to the TGN.•Viral particle-harboring vesicles segregate from the TGN for microtubule-mediated transport to the condensed chromosomes during mitosis.•Release of viral genome occurs after nuclear reformation and results in the association with PML nuclear bodies.

The non-enveloped human papillomaviruses (HPVs) specifically target epithelial cells of the skin and mucosa. Successful infection requires a lesion in the stratified tissue for access to the basal cells. Herein, we discuss our recent progress in understanding binding, internalization, uncoating, and intracellular trafficking of HPV particles. Our focus will be on HPV type 16, which is the most common HPV type associated with various anogenital and oropharyngeal carcinomas. The study of HPV entry has revealed a number of novel cellular pathways utilized during infection. These include but are not restricted to the following: a previously uncharacterized form of endocytosis, membrane penetration by a capsid protein, the use of retromer complexes for trafficking to the trans-Golgi network, the requirement for nuclear envelope breakdown and microtubule-mediated transport during mitosis for nuclear entry, the existence of membrane-bound intranuclear vesicles harboring HPV genome, and the requirement of PML protein for efficient transcription of incoming viral genome. The continued study of these pathways may reveal new roles in basic biological cellular processes.

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