Human papillomaviruses (HPV) cause nearly 5% of all human cancers, including cervical and oropharyngeal cancers. Two major viral oncoproteins, E6 and E7, are responsible for cell transformation and cancer development. Recent studies have identified a novel function of HPV proteins in regulating host protein transport pathways, particularly with respect to the sorting nexins SNX27 and SNX17. Our preliminary data show that HPV E6 and L2 proteins alter the transport of host cargo proteins, therefore supporting our hypothesis that HPV infection could directly interfere with host cell protein localization and transport, thus having broader implications for cell physiology and pathophysiology. This topic is highly innovative as the importance of these processes has only recently been highlighted and is still largely unknown. Our objective is to elucidate how HPV proteins modulate protein trafficking and to define the biological consequences thereof. This will be done by detailed biochemical characterization of HPV-protein interactions with the host trafficking machinery and by linking the contribution of these interactions to HPV-driven tumorigenesis. To this end, we will apply standard biochemical and cell biology methods, which will be augmented by modern approaches in in vivo imaging, 3D organotypic raft cultures and clinical sample analysis. The results of this study will define whether targeting interactions between HPV proteins and the host trafficking machinery could have potential prophylactic or therapeutic value in HPV-related pathologies. Furthermore, these studies will provide a list of potential diagnostic and prognostic biomarkers - cellular proteins whose expression patterns are altered during HPV infections and malignancies. This is particularly important for head and neck HPV cancers, where the disease burden resulting from HPV infections is likely to increase, while reliable diagnostic and prognostic markers are still missing.